HMG-CoA Reductase Inhibitors General Statement (Monograph)

Drug class: HMG-CoA Reductase Inhibitors
- Statins
VA class: CV350

Introduction

Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are antilipemic agents that competitively inhibit HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid, an early precursor of cholesterol.

General Principles of Antilipemic Therapy

Rationale for Intervention

Results of numerous epidemiologic studies indicate that elevated serum cholesterol, especially the low-density lipoprotein (LDL)-cholesterol fraction, is a major cause of clinical atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease (CHD), stroke, and peripheral arterial disease. Clinical, epidemiologic, and angiographic evidence from primary and secondary prevention studies involving various HMG-CoA reductase inhibitors (statins) indicates that decreasing elevated serum cholesterol concentrations (specifically, LDL-cholesterol) can reduce the incidence of ASCVD events and/or the progression of atherosclerosis and result in a decrease in associated morbidity and mortality. It has been estimated that each 1% reduction in LDL-cholesterol concentration may result in a 1% decrease in the incidence of CHD. An analysis of pooled data from primary and secondary prevention studies found that treatment with a statin for a median duration of 5.4 years was associated with 31 and 21% reductions in the risk of major coronary events (i.e., coronary death, fatal or nonfatal myocardial infarction [MI], unstable angina, sudden cardiac death) and total mortality, respectively. This represents an absolute risk reduction of 36 major coronary events and 16 deaths from all causes per 1000 patients. The risk reduction in major coronary events was similar among men (31%), women (29%), and geriatric (65 years of age and older) patients (32%). Data from secondary prevention studies involving various statins (e.g., atorvastatin, pravastatin, simvastatin) indicate that decreasing elevated serum cholesterol concentrations reduces the risk of fatal and nonfatal cerebrovascular events (e.g., stroke, transient ischemic attack [TIA]). An analysis of pooled data from clinical trials of statins indicates that patients receiving statin therapy had a 29% reduction in the risk of stroke and a 22% reduction in total mortality, which was attributable to a 28% reduction in CHD death. In a prospective meta-analysis conducted by the Cholesterol Treatment Trialists' (CTT) Collaboration, which included data from approximately 90,000 patients in 14 randomized studies of statins, the risk of major coronary events, revascularization, and stroke was found to be reduced by about one-fifth for each 1 mmol/L (38.7 mg/dL) reduction in LDL cholesterol achieved. Findings from the CTT meta-analysis inform the basis of many of the treatment recommendations regarding the use of statin therapy in cardiovascular risk reduction. Results of this and other studies showed that further reduction in LDL-cholesterol concentrations (e.g., more intensive statin therapy) produced greater cardiovascular risk reduction benefits. Clinical studies with statin therapy have not identified substantial adverse effects from LDL-cholesterol lowering per se; therefore, the decision to achieve very low LDL-cholesterol concentrations in very high-risk patients should be based on evidence of benefit and recognition that there appears to be only a remote possibility of adverse effects from LDL-cholesterol lowering.

Data from observational epidemiologic studies have indicated a strong inverse relationship between high-density lipoprotein (HDL)-cholesterol and the incidence of CHD; a lower HDL-cholesterol concentration correlates with higher CHD risk across levels of LDL-cholesterol of 100–200 mg/dL. It has been estimated that each 4-mg/dL reduction in HDL-cholesterol concentration may result in a 10% increase in the incidence of CHD. It is not clear whether increasing HDL-cholesterol concentration reduces the risk of cardiovascular events; however, data from large randomized studies in patients with established cardiovascular disease indicate that addition of niacin to existing statin-based therapy did not further reduce the incidence of major cardiovascular events compared with statin-based therapy alone. (See Secondary Prevention under Uses.)

Risk Assessment

Prior to initiating antilipemic therapy, patients should be evaluated for their risk of ASCVD. A risk assessment is particularly important for the appropriate selection of candidates for primary prevention.

Previous cholesterol management guidelines from the National Cholesterol Education Program (NCEP) identified 4 categories of risk based on the presence of CHD or CHD risk equivalents (e.g., abdominal aortic aneurysm, diabetes mellitus, peripheral arterial disease, renal artery disease, symptomatic carotid artery disease) and the presence or absence of major risk factors (e.g., smoking, hypertension, low HDL-cholesterol concentrations, family history of premature CHD, age); the 10-year risk of CHD also was estimated and included in the risk stratification system using Framingham projections.

More recent cholesterol management guidelines developed by the American College of Cardiology (ACC) and American Heart Association (AHA) identified 4 statin benefit groups: patients with clinical ASCVD (i.e., acute coronary syndromes [ACS], history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, peripheral arterial disease presumed to be of atherosclerotic origin); patients with primary, severe elevations in LDL-cholesterol concentration (190 mg/dL or greater); patients 40–75 years of age with diabetes mellitus; and patients without clinical ASCVD or diabetes mellitus who have LDL-cholesterol concentrations of 70–189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. The 2013 ACC/AHA cholesterol management guideline recommended the use of a global ASCVD risk assessment to guide initiation of statin therapy and introduced the concept of using the Pooled Cohort Equations to estimate 10-year risk of ASCVD (defined as first occurrence of nonfatal MI, CHD death, or nonfatal and fatal stroke). The Pooled Cohort Equations, which were developed with data from 5 longitudinal, population-based studies in geographically diverse patient populations (i.e., African American and non-Hispanic White men and women), predict the risk of a first ASCVD event on the basis of age, gender, race, smoking status, total cholesterol concentration, HDL-cholesterol concentration, systolic blood pressure, use of antihypertensive therapy, and diabetes mellitus. Although risk assessment equations such as the Pooled Cohort Equations and Framingham risk scoring system are useful, they may overestimate or underestimate the risk in individual patients; therefore, continuous refinement and improvement are necessary to optimize their application to clinical decision making. The importance of considering individual risk factors in a shared decision making process between the patient and clinician is emphasized in current cholesterol management guidelines.

Determination of LDL-cholesterol Concentrations and Target Goals

Adults

Previous cholesterol management guidelines by NCEP recommended a treat-to-target approach in which regular measurements of lipoprotein concentrations were required and used to monitor response to antilipemic therapy. The 2013 ACC/AHA cholesterol management guideline recommended a different approach, focusing on the intensity of statin therapy and relative reductions in LDL cholesterol rather than on specific LDL-cholesterol targets to guide therapy; the major shift was attributed in part to concerns about relying principally on randomized, controlled studies to inform the evidence. Although the 2018 update of the AHA/ACC guideline retains some of the concepts introduced in 2013, such as statin intensities, the updated guideline incorporates LDL thresholds back into certain decisions, including add-on nonstatin therapies in certain high-risk patients.

The current AHA/ACC cholesterol management guideline recommends that a fasting lipoprotein profile be obtained in adults prior to initiation of antilipemic (i.e., statin) therapy, 4–12 weeks after initiation of antilipemic therapy or after dosage adjustments (to determine the patient’s response to therapy and adherence), and every 3–12 months thereafter as clinically indicated.

Pediatric Patients

There is no clear consensus on screening pediatric patients for lipid disorders. According to the NCEP expert panel, American Academy of Pediatrics (AAP), and AHA, a lipoprotein profile (preferably under fasting conditions) should be performed once every 5 years in children older than 2 years of age at high risk of developing dyslipidemia as adults (i.e., family history of premature cardiovascular disease [including CHD, atherosclerosis, peripheral vascular disease, cerebrovascular disease, MI], family history of dyslipidemia, presence of major risk factors [including obesity, hypertension, cigarette smoking, diabetes mellitus]) or in those for whom a family history is unavailable. However, studies have shown that this targeted screening approach will miss 30–60% of pediatric patients with elevated cholesterol concentrations. Therefore, an expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents recommends universal screening (nonfasting lipoprotein profile with non-HDL-cholesterol concentrations) in all children 9–11 years of age and 17–21 years of age.

Thresholds for therapy considerations and target LDL-cholesterol goals vary among pediatric guidelines, and clinicians are encouraged to consult individual guidelines for additional information. According to the AAP Committee on Nutrition, AHA, and the NCEP expert panel on blood cholesterol concentrations in children and adolescents, dietary measures should be considered in all adolescents and children 2 years of age and older who have LDL-cholesterol concentrations exceeding 110 mg/dL. The AHA, NCEP expert panel, and the expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents state that antilipemic drug therapy should be reserved for children 10 years of age and older who, despite strict dietary management, have a serum LDL-cholesterol concentration of 190 mg/dL or greater or a serum LDL-cholesterol concentration of 160 mg/dL or greater and either a family history of definite premature cardiovascular disease (e.g., CHD, cerebrovascular or occlusive peripheral vascular disease) or at least 2 other risk factors (i.e., cigarette smoking, hypertension, low serum HDL-cholesterol concentrations, diabetes mellitus, severe obesity [30% or more overweight], physical inactivity) despite an adequate trial (6–12 months) of dietary management. The AAP supports the above thresholds but states that antilipemic therapy may be initiated in children as young as 8 years of age. The AAP also states that antilipemic therapy may be considered in children 8 years of age and older who have diabetes mellitus and a serum LDL-cholesterol concentration of 130 mg/dL or greater; AHA and the expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents state that antilipemic therapy may be considered in selected children younger than 10 years of age who have severe lipid abnormalities along with other risk factors and/or high-risk conditions (e.g., diabetes mellitus). Although antilipemic therapy may be initiated at a younger age in selected children who have extremely high cholesterol concentrations, the NCEP expert panel states that only a small proportion of children and adolescents should be considered for drug therapy because of the adverse effects, expense, and the lack of definitive, prospective data on the effects of such treatment on coronary heart disease. (See Pediatric Precautions under Cautions.) The AHA and the NCEP expert panel state that the minimum goal of dietary or drug therapy in children 2 years of age and older and adolescents is to achieve an LDL-cholesterol concentration of less than 130 mg/dL or, if possible, less than 110 mg/dL. The AAP states that these target goals may be warranted in patients with a strong family history of cardiovascular disease or in those with multiple risk factors.

Treatment Recommendations

Adults

The goal of antilipemic therapy is to reduce the risk of ASCVD. The intensity of therapy is guided by the initial risk status of the patient, with the most intensive approach reserved for those with established clinical ASCVD and those at high risk of ASCVD (e.g., patients with markedly elevated LDL-cholesterol concentrations, patients with diabetes mellitus and additional risk factors). Lifestyle modification therapies are the foundation of ASCVD risk reduction and continue to be emphasized in current cholesterol management guidelines. Drug therapy is not a substitute for but an adjunct to nondrug therapies and measures, which should be continued when drug therapy is initiated.

There is extensive evidence demonstrating that statins can substantially reduce the risk of ASCVD across a broad population of patients, and therefore these drugs are considered the drugs of choice for reducing high LDL-cholesterol concentrations and the associated risk of cardiovascular events. Because the relative risk reduction is correlated with the degree of LDL-cholesterol lowering, the maximum tolerated statin intensity should be used to achieve optimum ASCVD benefits. The intensity of statin therapy is divided into 3 categories based on the degree of LDL lowering (low-intensity therapy is less than 30%, moderate-intensity therapy is 30–49%, and high-intensity therapy is 50% or more reduction). Although moderate-intensity statin therapy also has been shown to reduce the risk of ASCVD, high-intensity statin therapy can provide a greater risk reduction benefit and is therefore preferred. If high-intensity statin therapy is not possible because of a contraindication or adverse effect, the maximum tolerated statin therapy should be used. According to the AHA/ACC guideline, high-intensity statin therapy includes atorvastatin 40–80 mg daily or rosuvastatin 20–40 mg daily; moderate-intensity statin therapy includes atorvastatin 10–20 mg daily, fluvastatin 40 mg twice daily (as an immediate-release formulation) or 80 mg daily (as extended-release tablets), lovastatin 40–80 mg daily, pitavastatin 1–4 mg daily, pravastatin 40–80 mg daily, rosuvastatin 5–10 mg daily, or simvastatin 20–40 mg daily. Some of these statin regimens were specifically evaluated in randomized controlled studies demonstrating a reduction in major cardiovascular events, while others are consistent with FDA-labeled dosages, but were not evaluated in the randomized controlled studies reviewed by the AHA/ACC expert panel.

Most patients with ASCVD can be treated with statins alone; however, consideration may be given to adding a nonstatin drug in certain high-risk patients (e.g., patients with very high risk of ASCVD, LDL-cholesterol concentrations of 190 mg/dL or greater, or diabetes mellitus and additional risk factors) who do not achieve adequate reductions in LDL-cholesterol concentrations with maximally tolerated statin therapy. Nonstatin drugs that may be considered include ezetimibe or a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor (or possibly both) depending on the specific situation. Selection of a nonstatin drug should be based on a favorable benefit-risk ratio (i.e., demonstrated benefit of ASCVD risk reduction outweighs risks of adverse effects) and patient preferences. Response to therapy should be evaluated 4–12 weeks after initiation of statin therapy or combination therapy. The maximum percent change in LDL-cholesterol concentrations generally occurs within this time frame.

Secondary Prevention in Adults with Clinical ASCVD

The 2018 AHA/ACC cholesterol management guideline states that patients 75 years of age or younger with clinical ASCVD (defined as those with ACS, history of MI, stable or unstable angina or coronary or other arterial revascularization, stroke, TIA, or peripheral artery disease) should be treated with a statin in conjunction with lifestyle modification to reduce LDL-cholesterol concentrations. Because patients older than 75 years of age may have a higher risk of adverse effects and lower adherence to therapy, the expected benefits versus adverse effects of statin therapy should be considered before initiating statin therapy in this population. The relative reduction in ASCVD risk is correlated with the degree of LDL-cholesterol reduction; therefore, the maximum tolerated intensity of a statin should be used. The AHA/ACC cholesterol management guideline recommends the use of high-intensity statin therapy (producing reductions in LDL-cholesterol concentrations of at least 50%) in patients with clinical ASCVD. If high-intensity statin therapy is not possible because of a contraindication or adverse effect, a moderate-intensity statin (producing reductions in LDL-cholesterol concentrations of 30–49%) may be used.

In very high-risk patients (e.g., those with a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions), an LDL-cholesterol threshold of 70 mg/dL may be used to consider the addition of nonstatin drugs to statin therapy; additional benefit may be obtained by further reducing LDL concentrations in these patients. The AHA/ACC cholesterol management guideline states that in very high-risk patients, it is reasonable to add ezetimibe to maximally tolerated statin therapy when the LDL-cholesterol concentration remains at or above 70 mg/dL; additional treatment with a PCSK9 inhibitor may be considered, if needed, after discussing the net benefits, safety, and costs with the patient.

Primary Prevention in Adults with Primary Severe Elevations in LDL-cholesterol Concentration (190 mg/dL or Greater)

Adults with severe elevations in LDL-cholesterol concentration (190 mg/dL or higher) have a high lifetime risk for ASCVD and recurrent or premature coronary events. Therefore, these patients require substantial reductions in LDL-cholesterol concentrations and intensive management of other risk factors to reduce ASCVD risk. Regardless of whether the patient is found to have a genetic mutation associated with familial hypercholesterolemia, patients with very high LDL concentrations are most likely to achieve the greatest benefit from evidence-based LDL-lowering therapy. Although there are no controlled studies involving only patients with LDL-cholesterol concentrations of 190 mg/dL or higher, many studies evaluating statin therapy did include these patients, and all of these studies consistently demonstrated a reduction in ASCVD events. Therefore, the 2018 AHA/ACC cholesterol management guideline recommends that all patients 20–75 years of age with LDL-cholesterol concentrations of 190 mg/dL or higher receive maximally-tolerated statin therapy in conjunction with lifestyle modifications. If the LDL-cholesterol concentration remains at or above 100 mg/dL or is not reduced by at least 50% while receiving maximally tolerated statin therapy, ezetimibe may be considered as add-on therapy; although evidence is more limited, additional treatment with a PCSK9 inhibitor may be considered, if needed, after discussing the net benefits, safety, and costs with the patient.

Primary Prevention in Adults with Diabetes Mellitus

Diabetes mellitus is an independent risk factor for cardiovascular disease (e.g., atherosclerotic CHD, diabetic cardiomyopathy, cerebrovascular disease, peripheral vascular disease). Because diabetes mellitus often is associated with hyperglycemia, atherogenic dyslipidemia (i.e., presence of elevated triglycerides, small dense LDL particles, and low HDL-cholesterol), and other lipid and nonlipid risk factors of the metabolic syndrome, the risk for major coronary events (MI and CHD death) in patients with diabetes mellitus has been found to be similar to that in nondiabetic patients with CHD. In addition, patients 40–75 years of age with diabetes mellitus have a substantially increased lifetime risk for ASCVD events and death, and such patients experience greater morbidity and worse survival following the onset of clinical ASCVD.

Primary prevention trials have demonstrated benefit with moderate-intensity statin therapy in large cohorts of patients with diabetes mellitus. Based on these findings, the 2018 AHA/ACC cholesterol management guideline recommends treatment with a moderate-intensity statin in adults 40–75 years of age with diabetes mellitus regardless of their estimated 10-year risk of ASCVD. However, given the evidence of benefit with high-intensity statin therapy and the increased risk of morbidity and mortality associated with a first ASCVD event in patients with diabetes mellitus, the guidelines state that high-intensity is preferred in these patients as they age or if they have additional ASCVD risk factors. In patients with diabetes mellitus who are younger than 40 years of age or older than 75 years of age, the potential benefits versus adverse effects, drug interactions, and patient preferences should be considered when deciding to initiate, continue, or intensify statin therapy.

Primary Prevention in Adults without Diabetes Mellitus

The 2013 ACC/AHA cholesterol management guideline recommendations regarding primary prevention was controversial, recommending statin therapy based on 10-year ASCVD risk without considering baseline LDL-cholesterol concentration. Some clinicians predicted that wide implementation of the recommendations would lead to overtreatment, possibly resulting in an increased incidence of statin-related adverse effects (e.g., myositis, rhabdomyolysis). The 2018 AHA/ACC cholesterol management guideline emphasizes the importance of a patient-clinician discussion regarding major risk factors and benefits versus risks of statin therapy. In adults 40–75 years of age without diabetes mellitus, but with LDL-cholesterol levels of 70 mg/dL or greater and an estimated 10-year ASCVD risk of 7.5% or more, moderate-intensity statin therapy may be initiated if the discussion of treatment options favors statin therapy.

Metabolic Syndrome

The principal goals of therapy in the management of the metabolic syndrome are treatment of the underlying causes (i.e., obesity, physical inactivity) and management of other associated lipid and nonlipid risk factors. Weight reduction and increased physical activity generally are considered first-line therapies for the management of the metabolic syndrome. These measures, which effectively reduce most lipid and nonlipid risk factors, should be emphasized after appropriate control of LDL cholesterol. Weight reduction can enhance LDL-cholesterol lowering, while regular physical activity can reduce very-low-density lipoprotein (VLDL)-cholesterol (and, in some patients, LDL-cholesterol) concentrations, increase HDL-cholesterol concentrations, lower blood pressure, reduce insulin resistance, and favorably influence cardiovascular function.

Management of other associated lipid and nonlipid risk factors also should be considered in patients with clinical evidence of the metabolic syndrome. These measures include treatment of hypertension, use of aspirin in patients with CHD to reduce the prothrombotic state, and management of elevated triglycerides and low HDL-cholesterol concentrations.

Hypertriglyceridemia

Pooled analysis of data from prospective studies indicates that elevated serum triglycerides, particularly when coupled with low HDL cholesterol and a predominance of small, dense LDL particles (i.e., the lipid triad) are an independent risk factor for CHD. Elevated serum triglycerides have been found to increase the risk of developing hypertension and insulin resistance and to promote atherogenesis by inducing a prothrombotic state (i.e., increased platelet aggregability, elevated fibrinogen concentrations, increased plasminogen activator inhibitors [PAI], increased factor VII, and increased factor X clotting activity). This lipid abnormality most often is observed in individuals with the metabolic syndrome. In patients with severe hypertriglyceridemia, elevations in atherogenic VLDL-cholesterol concentrations may increase the risk of ASCVD.

The 2018 AHA/ACC cholesterol management guideline recommends nonpharmacologic therapy (e.g., lifestyle modification) and management of underlying factors whenever possible in adults with moderate hypertriglyceridemia (fasting or nonfasting triglyceride concentrations of 175–499 mg/dL). Because most patients with severe hypertriglyceridemia (fasting triglyceride concentrations of 500 mg/dL or greater) have multiple risk factors for ASCVD and are at increased risk of developing atherosclerotic disease, the guidelines state that it is reasonable to initiate statin therapy in selected patients with severe hypertriglyceridemia. Patients with persistently high triglyceride concentrations (500 mg/dL or greater), particularly those with triglyceride concentrations exceeding 1000 mg/dL, may require additional measures (e.g., implementation of a very low-fat diet, avoidance of refined carbohydrates and alcohol, consumption of omega-3-fatty acids, and fibric acid therapy if necessary) to prevent development of acute pancreatitis. Concomitant use of statins with a fibric acid derivative (i.e., fenofibrate) requires reduction in the daily dosage of the statin and should be undertaken with extreme caution to minimize the potential risk of myopathy and/or rhabdomyolysis. In addition, some clinicians state that such combined regimens generally should be avoided in geriatric patients, in patients with acute or serious chronic illnesses (especially chronic renal disease), in patients undergoing surgery, and in patients receiving certain interacting medications. (See Precautions and Contraindications under Cautions and also see Antilipemic Agents under Drug Interactions.)

Low HDL Cholesterol

Low HDL-cholesterol concentrations (less than 40 mg/dL) have historically been considered a strong independent risk factor for CHD. Although some clinicians have previously stated that therapeutic decisions should take into account the level of HDL cholesterol, and the use of agents that raise HDL cholesterol should be considered if antilipemic drug therapy is needed in a patient who has both high LDL-cholesterol and low HDL-cholesterol concentrations, current evidence indicates that reduced HDL cholesterol is a component of the metabolic syndrome for which lifestyle therapies are particularly indicated. HDL-cholesterol concentrations also are included in certain risk estimate equations for ASCVD and taken into account when determining whether statin therapy is indicated in a patient.

Patients with HIV Infection

Human immunodeficiency virus (HIV) infection is an independent risk factor for cardiovascular disease. In addition, long-term use of antiretroviral therapies has been associated with an increased risk of MI. Certain antiretroviral therapies such as older-generation protease inhibitors (PIs) can cause dyslipidemias. Data from several observational studies indicate an association between some HIV PIs and an increased risk of cardiovascular events. Improved lipid profiles and reduced mortality have been reported in observational studies of HIV patients receiving statin therapy.

The 2018 AHA/ACC cholesterol management guideline states that moderate-intensity statin therapy or high-intensity statin therapy may be of some benefit in adults 40–75 years of age with HIV who have LDL-cholesterol concentrations of 70–189 mg/dL and a 10-year ASCVD risk of 7.5% or higher. A fasting lipid profile and assessment of ASCVD risk factors may be used to gauge the benefits of statin therapy and to monitor or adjust lipid-lowering therapy.

Children and Adolescents

In children, adolescents, and young adults, emphasis should be given to reducing lifetime ASCVD risk through lifestyle modifications, including dietary management (e.g., restriction of total and saturated fat and cholesterol intake), weight control, an appropriate physical activity program, and management of potentially contributory disease. The National Heart, Lung, and Blood Institute (NHLBI)-appointed expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents recommends that the Cardiovascular Health Integrated Lifestyle Diet (CHILD)-1 diet (intake of 25–30% of total calories from fat, with 8–10% of total calories from saturated fatty acids, and intake of less than 300 mg of cholesterol daily) be initiated in all children 2 years of age or older and adolescents who have LDL-cholesterol concentrations exceeding 130 mg/dL. A CHILD-2 diet (intake of 25–30% of total calories from fat, with 7% or less of total calories from saturated fatty acids, and intake of less than 200 mg of cholesterol daily) may be considered after 3 months in patients whose LDL-cholesterol concentrations remain at 130 mg/dL or greater.

Experts state that pharmacologic therapy generally should be limited to selected patients who have serum LDL-cholesterol concentrations of 190 mg/dL or greater or those who have LDL-cholesterol concentrations of 160 mg/dL or greater and either a family history of premature cardiovascular disease or multiple risk factors despite an adequate trial of dietary management. The NHLBI expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents states that statin therapy should be considered in high-risk patients 10 years of age older only after a 6-month trial of dietary and lifestyle management.

Recommendations for selection of antilipemic drug therapy vary among pediatric guidelines, and clinicians are encouraged to consult individual guidelines for additional information. The AHA/ACC cholesterol management guidelines state that it is reasonable to consider initiation of statin therapy in children and adolescents 10 years of age or older with LDL-cholesterol concentrations of 190 mg/dL or higher or 160 mg/dL or higher and a clinical presentation of familial hypercholesterolemia who do not respond adequately to 3–6 months of lifestyle therapy. Fibric acid derivatives have not been extensively studied in children and, therefore, should be used cautiously and preferentially in children with severe elevations in triglyceride concentration who are at risk of developing pancreatitis. Cholesterol absorption inhibitors (i.e., ezetimibe) may potentially become an important treatment option; however, additional studies are needed to evaluate their use as monotherapy and their long-term effectiveness in pediatric patients.

For additional details on management of dyslipidemias in pediatric patients, consult the most recent Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents (available at [Web]).

Uses for HMG-CoA Reductase Inhibitors General Statement

Overview

HMG-CoA reductase inhibitors (statins) are used as adjuncts to nondrug therapies (i.e., lifestyle modifications) to reduce the risk of clinical ASCVD, which includes ACS, history of MI, stable or unstable angina or coronary or other arterial revascularization, stroke, TIA, or peripheral artery disease.

Statins also are used as adjuncts to nondrug therapies (e.g., dietary management) in the management of specific dyslipidemias, including primary hypercholesterolemia or mixed dyslipidemia, homozygous familial hypercholesterolemia, primary dysbetalipoproteinemia, and hypertriglyceridemia.

Statins are considered first-line pharmacologic therapy for primary or secondary prevention of ASCVD in patients with established ASCVD or in patients with elevated risk of ASCVD. Reductions in LDL-cholesterol concentrations with statins generally exceed those attainable with recommended dosages of other antilipemic agents, including bile acid sequestrants, niacin, and fibric acid derivatives (e.g., gemfibrozil). (See Primary Hypercholesterolemia or Mixed Dyslipidemia under Uses.) When given as monotherapy for primary or secondary prevention of CHD, statins have been shown to reduce the incidence of coronary events by approximately 24–37% and the risk of death from any cause by about 22–30%. Statin therapy also reduces the risk of angina pectoris, cerebrovascular accidents, and the need for coronary revascularization procedures (e.g., coronary artery bypass grafting [CABG], angioplasty).

Results of comparative clinical studies using recommended dosages of various statins indicate that these agents differ in lipid-lowering as well as non-lipid-lowering effects. Reductions in LDL-cholesterol concentrations averaging 27–60, 25–42, 17–36, 21–48, 31–45, 19–41, 45–63, and 26–51% have been reported with recommended daily dosages of atorvastatin, cerivastatin (no longer commercially available in the US), fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, respectively, in patients with various forms of dyslipidemia who received statin therapy for at least 6 weeks. While atorvastatin and rosuvastatin generally have produced greater reductions in total and LDL-cholesterol, apolipoprotein B (apo B), and triglycerides than equipotent dosages of other statins, the superiority of a given statin in terms of improvement in cardiovascular outcomes compared with other drugs in this class has not been clearly defined to date. However, pooled analysis of data from trials in which various statins were used for primary or secondary prevention of cardiovascular events or for reducing progression of atherosclerotic plaques indicate similar reductions in death and major cardiovascular events despite differences in the effects of these statins on cholesterol components. It has been suggested that these benefits may result from antilipemic as well as pleiotropic effects (e.g., inhibition of arterial smooth muscle cell proliferation, stabilization of atherosclerotic plaques) of statins. (See Pharmacology.) In addition, factors other than antilipemic potency, such as baseline LDL-cholesterol concentration, baseline CHD risk, time of assessment of clinical benefit (i.e., early angiographic improvement may not translate into clinical improvement for several years), or other characteristics of the study population also may affect outcome in clinical trials of patients receiving statin therapy. Further study is needed to determine the impact of differences in antilipemic and pleiotropic effects of statins on clinical outcomes.

Reduction in Risk of Cardiovascular Events

Primary Prevention

Statins are used as adjuncts to lifestyle modification to reduce the risk of a first major acute coronary event (e.g., MI, unstable angina, coronary revascularization procedure, coronary death, stroke) in patients without clinical ASCVD (primary prevention). For additional details regarding the use of specific statins, see the individual statin monographs in 24:06.08.

In a randomized, double-blind, placebo-controlled study (West of Scotland Coronary Prevention Study [WOSCOPS]) in men with moderate hypercholesterolemia and no history of MI, therapy with pravastatin (40 mg daily) for a median of 4.9 years lowered total and LDL-cholesterol by 20 and 26%, respectively, and reduced the incidence of MI and death from cardiovascular causes by approximately 31%; the risks of undergoing coronary angiography and myocardial revascularization procedures also were reduced by 31 and 37%, respectively. In another randomized, double-blind, placebo-controlled study (Air Force/Texas Coronary Atherosclerosis Prevention Study [AFCAPS/TexCAPS]) in men and women (45–73 years of age) with average or moderately elevated total and LDL-cholesterol and below-average HDL-cholesterol concentrations (i.e., 36–40 mg/dL), treatment with lovastatin (20–40 mg daily) for a median of 5.2 years reduced the incidence of first acute major coronary events (defined as fatal or nonfatal MI, unstable angina, or sudden cardiac death) by 37% and the need for revascularization procedures by 33%. Clinical benefit was achieved within 1 year of initiating therapy and continued throughout the remainder of the study.

Despite favorable findings from the WOSCOPS and AFCAPS/TexCAPS studies, clinical benefit (i.e., reduction in CHD-related morbidity or all-cause mortality) was not observed in a randomized, open-label study, the Lipid Lowering Trial (LLT), in a subset of patients from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). In this study (ALLHAT-LLT) in patients 55 years of age or older with well-controlled hypertension and moderately elevated LDL-cholesterol concentrations, the incidence of all-cause mortality or CHD-related adverse events (i.e., CHD death, nonfatal MI, stroke, congestive heart failure) was similar among patients receiving pravastatin (40 mg daily) or usual care (i.e., moderate LDL-cholesterol lowering according to the discretion of the patient’s primary care clinician) for a mean duration of 4.8 years. The lack of clinical benefit may be attributable to the modest difference in total and LDL-cholesterol reduction between pravastatin and usual care recipients (17 versus 8% reduction in total cholesterol and 28 versus 11% reduction in LDL-cholesterol) compared with the differences reported in other statin trials. This modest difference may have resulted from poor adherence to initially prescribed therapy; at year 6 of follow-up, only 70% of patients randomized to receive pravastatin were still taking the protocol-specified dosage (40 mg daily), while 28.5% of patients randomized to receive usual care were receiving antilipemic therapy (26.1% with a statin). Despite the reported lack of clinical benefit in this study, study results are consistent with previous findings indicating that lesser degrees of cholesterol lowering are associated with less clinical benefit. Adherence to treatment should be particularly emphasized when antilipemic therapy is implemented in routine clinical practice in order to achieve adequate reduction in LDL-cholesterol concentrations.

Results of a pooled analysis of randomized, controlled trials in patients (90% without clinical evidence of CHD) who are at moderate to moderately high risk of developing CHD indicate that treatment with a statin over a mean of 4.3 years substantially reduced the relative risk of major coronary events (including nonfatal MI) by 29.2%, major cerebrovascular events by 14.4%, and revascularization procedures by 33.8%, but not CHD or overall mortality, compared with placebo. Statin therapy did not appear to increase the risk of cancer or increase concentrations of aminotransferase or creatine kinase (CK, creatine phosphokinase, CPK), although the confidence intervals for these safety measures were very wide. Although the relative risk reductions observed in this study were similar to those reported in secondary prevention studies, the absolute benefit is substantially lower because of the lower risk in primary prevention patients. Some clinicians state that statins appear to be cost-effective for primary prevention in patients at high risk of developing CHD (10-year risk exceeding 20%) but cost-ineffective in patients at low risk (10-year risk of less than 10%); further studies are needed to clarify the cost-effectiveness of statin therapy for primary prevention in patients at moderately high risk of developing CHD (10-year risk of 10–20%).

Patients with Diabetes Mellitus

Statins are used as adjuncts to nondrug therapies (e.g., dietary management) to decrease elevated serum total and LDL-cholesterol concentrations and to reduce the risk of initial or recurrent acute coronary events (primary or secondary prevention, respectively) in patients with diabetes mellitus.

In the Collaborative Atorvastatin Diabetes Study (CARDS) in hypercholesterolemic patients (median total cholesterol concentration of 207 mg/dL, LDL-cholesterol concentration of 120 mg/dL, triglyceride concentration of 151 mg/dL) with type 2 diabetes mellitus (mean hemoglobin A_1c [HbA_1c] of 7.7%) and at least one other risk factor (e.g., smoking, hypertension, retinopathy, microalbuminuria, macroalbuminuria), therapy with atorvastatin (10 mg daily) for a median of 3.9 years reduced the risk of stroke by 48% and the risk of MI by 42% compared with placebo. Lipoprotein concentrations were lowered to levels similar to those observed with atorvastatin 10 mg daily in previous clinical studies. Treatment with atorvastatin did not reduce the risk of unstable angina, revascularization procedures, or acute CHD death.

Several subgroup analyses evaluating the benefits of statins in patients with established CHD and mildly elevated fasting glucose concentrations or diabetes mellitus have reported improvements in the risk of cardiovascular events, as evidenced by reductions in the risks of recurrent coronary events and revascularization procedures. In several subgroup analyses evaluating effects of statin therapy in CHD patients with elevated cholesterol concentrations and normal fasting glucose (defined as fasting plasma glucose concentrations less than 110 mg/dL [6 mmol/L]), impaired fasting glucose (defined as fasting plasma glucose concentrations between 110 and 126 mg/dL [6–7 mmol/L]), or diabetes mellitus (defined as fasting plasma glucose concentrations equal to or exceeding 126 mg/dL [7 mmol/L] with or without a clinical history of diabetes mellitus), treatment with pravastatin (40 mg daily) or simvastatin (40 mg daily) for at least 5 years was associated with reductions in the risk of major coronary events (23–32, 38, and 25–42% in patients with normal fasting glucose, impaired fasting glucose, and those with diabetes mellitus, respectively) and the risk of undergoing myocardial revascularization procedures (33, 43, and 32–48%, respectively). The risk of total mortality and coronary mortality was markedly reduced in patients with normal fasting glucose (28 and 42%, respectively) and impaired fasting glucose (43 and 55%, respectively) but was only modestly reduced in diabetic patients (21 and 28%, respectively).

The addition of fenofibrate to statin therapy has not been shown to provide an incremental benefit on cardiovascular morbidity and mortality beyond that already demonstrated with statin monotherapy. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD Lipid) Study, the combination of fenofibrate (160 mg daily) and a statin (simvastatin at dosages up to 40 mg daily) was compared with statin therapy alone in patients with type 2 diabetes mellitus at high risk for cardiovascular disease. Despite a favorable effect on serum lipid concentrations (e.g., increased HDL-cholesterol, reduced triglycerides), the addition of fenofibrate to simvastatin therapy did not substantially reduce the rate of major adverse cardiovascular events (i.e., nonfatal MI, nonfatal stroke, death from cardiovascular causes) compared with statin monotherapy over a mean follow-up period of 4.7 years. In general, routine use of fenofibrate in combination with a statin to further reduce ASCVD risk is not recommended in patients with type 2 diabetes mellitus; while subgroup analyses indicate that such a combination may provide some benefit in certain groups of patients (e.g., those with type 2 diabetes mellitus and atherogenic dyslipidemia), further study is required to confirm these findings.

Secondary Prevention

Statins are used as adjuncts to lifestyle modification in patients with established ASCVD to reduce the risk of recurrent ASCVD events (secondary prevention).

Several clinical trials designed to evaluate the benefits of statins in patients with established CHD, including prior MI and angina pectoris, have reported improvements in cardiovascular risk status, as evidenced by reductions in the risks of total mortality and nonfatal coronary events. In the Scandinavian Simvastatin Survival Study (4S), therapy with simvastatin (20–40 mg daily) in 4444 patients with hypercholesterolemia and angina pectoris or prior MI was associated with reductions in total mortality (30%), CHD mortality (42%), and hospital-verified nonfatal MI (37%) compared with placebo over a median of 5.4 years of follow-up; the risk of undergoing myocardial revascularization procedures also was reduced by 37%. In addition, simvastatin therapy reduced the risk of fatal and nonfatal cerebrovascular events (combined incidence of stroke and TIA) by 28%.

In the Heart Protection Study (HPS), therapy with simvastatin (40 mg daily) in over 20,000 patients with CHD, history of stroke, or other cerebrovascular disease, other occlusive arterial disease (e.g., peripheral arterial disease), hypertension, or diabetes mellitus reduced the risk of total mortality (13%), CHD mortality (18%), nonfatal MI (38%), ischemic stroke (25%), coronary revascularization procedures (30%), and peripheral and other noncoronary revascularization procedures (16%) compared with placebo over approximately 5 years of follow-up, irrespective of baseline lipoprotein concentrations.

In the Cholesterol and Recurrent Events (CARE) study, therapy with pravastatin (40 mg daily) in patients with prior MI and average cholesterol concentrations (baseline total, LDL-, and HDL-cholesterol concentrations averaging 209, 139, and 39 mg/dL, respectively) was associated with a 24% reduction in CHD mortality or nonfatal MI compared with placebo after an average follow-up period of approximately 5 years. Therapy with pravastatin also reduced the risk of undergoing myocardial revascularization procedures (e.g., coronary artery bypass grafting [CABG], percutaneous transluminal coronary angioplasty) by 27% and the risk of stroke or TIA by 26% (risk reduction of 31% for stroke alone). The reduction in combined coronary events was greater in women and in those with higher pretreatment LDL-cholesterol concentrations. In addition, risk reduction reported in the CARE trial also was observed in geriatric patients (65 years of age and older) and in patients who had undergone coronary revascularization.

In the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study, therapy with pravastatin (40 mg daily) in patients with a history of MI or hospitalization for unstable angina and normal or elevated total cholesterol concentrations resulted in reductions in overall mortality (22%), CHD mortality (24%), MI (29%), stroke (19%), and coronary revascularization procedures (20%) compared with placebo after an average follow-up period of 6.1 years.

Certain statins have been shown to reduce the risk of recurrent stroke. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study in hypercholesterolemic patients (LDL-cholesterol concentrations of 100–190 mg/dL) who had a stroke or TIA within the past 1–6 months, therapy with high-dose atorvastatin (80 mg daily) for a median of 4.9 years reduced the risk of subsequent nonfatal or fatal stroke and of major cardiovascular events by approximately 16 and 20%, respectively, compared with placebo. However, atorvastatin therapy did not reduce overall mortality. In addition, hemorrhagic stroke and elevated aminotransferase (transaminase) concentrations were reported in more patients receiving atorvastatin than in those receiving placebo; patients with a history of hemorrhagic stroke at study entry appeared to be at increased risk of developing hemorrhagic stroke. Some clinicians state that the results of this study should be interpreted with caution due to the heterogeneity of enrolled patients (i.e., with respect to stroke etiology and vascular risk). Furthermore, because patients with atrial fibrillation or other cardiac sources of embolism were excluded from the study, it is not known whether the observed benefits of atorvastatin apply to ischemic strokes of cardioembolic origin.

Intensive Statin Therapy for Stable CHD

Intensive antilipemic therapy (i.e., with atorvastatin 80 mg daily) has been shown to be more effective than moderate antilipemic therapy (i.e., with atorvastatin 10 mg daily) in reducing the risk of cardiovascular events in patients with stable CHD. In a randomized, double-blind, active-controlled study (Treating to New Targets [TNT]) in approximately 10,000 patients with clinically evident CHD (i.e., history of MI, history of or current angina with objective evidence of atherosclerotic CHD, history of coronary revascularization) and LDL-cholesterol concentrations less than 130 mg/dL, treatment with atorvastatin 80 or 10 mg daily for a median of 4.9 years reduced LDL-cholesterol concentrations to a mean of 77 or 101 mg/dL, respectively. Compared with the 10-mg daily regimen, treatment with the 80-mg daily regimen resulted in a 22% relative reduction in the composite risk of primary end points (i.e., death from CHD, nonfatal non-procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke). Of the events that comprised the primary composite endpoint, treatment with the intensive regimen substantially reduced the rate of nonfatal non-procedure-related MI and fatal and nonfatal stroke, but not death from CHD or resuscitated cardiac arrest. Of the predefined secondary endpoints, treatment with the intensive regimen reduced the rate of coronary revascularization, angina, and hospitalization for CHF, but not peripheral vascular disease. The intensive regimen did not reduce overall mortality and was associated with a slightly (but not statistically significant) increased risk of death from noncardiovascular causes. In addition, severe adverse effects (e.g., elevations in concentrations of aminotransferase or creatine kinase [CK, creatine phosphokinase, CPK] to at least 3 or 10 times greater than the upper limit of normal, respectively) and discontinuance of therapy due to adverse effects occurred more frequently in patients receiving the 80-mg daily regimen compared with the 10-mg daily regimen.

In a randomized, comparative study (Incremental Decrease in Endpoints through Aggressive Lipid Lowering [IDEAL]) in 8888 patients with a history of CHD and an average LDL-cholesterol concentration of approximately 122 mg/dL, treatment with atorvastatin (80 mg daily) or simvastatin (20–40 mg daily) for a median of 4.8 years resulted in similar reduction in the risk of the primary composite end point (i.e., fatal CHD, nonfatal MI, and resuscitated cardiac arrest). In addition, no difference in overall mortality was observed between atorvastatin- or simvastatin-treated patients, and the rates of death from cardiovascular or noncardiovascular causes were similar in both treatment groups.

Intensive Statin Therapy for CHD and the Metabolic Syndrome

Intensive antilipemic therapy (i.e., with atorvastatin 80 mg daily) has been shown to be more effective than moderate antilipemic therapy (i.e., with atorvastatin 10 mg daily) in reducing the risk of cardiovascular events in patients with CHD and the metabolic syndrome. In a post hoc analysis of the TNT study in 5584 patients with CHD and the metabolic syndrome, treatment with the intensive regimen was associated with a lower incidence of major cardiovascular events than treatment with the moderate regimen (9.5 versus 13%); this represented a 29% relative reduction in the risk of major cardiovascular events in favor of the intensive regimen. However, consistent with the overall population in the TNT study, the intensive regimen did not reduce overall mortality compared with the moderate regimen.

Early and Intensive Statin Therapy for Acute Coronary Syndromes

Intensive statin therapy has been shown to be more effective than lower-intensity regimens in reducing the risk of cardiovascular events in patients with ACS. In a randomized, double-blind study (A to Z trial) in about 4500 patients with manifestations of ACS within the preceding 5 days, early initiation of intensive antilipemic therapy (simvastatin 40 mg daily for 1 month, then simvastatin 80 mg daily) for 6–24 months resulted in a 25% reduction in the risk of cardiovascular mortality compared with delayed initiation of a less aggressive antilipemic regimen (placebo for 4 months, then simvastatin 20 mg daily thereafter). There was a reduction (11%) in the rate of the primary end point (a composite of cardiovascular death, nonfatal MI, readmission for ACS, and stroke) for the entire study period (not statistically significant). Although no difference was evident between the intensive and less aggressive regimens during the first 4 months of therapy, the primary end point was substantially reduced (by 25%) from month 4 through the end of the study in patients receiving the intensive regimen. Intensive or less aggressive antilipemic therapy reduced LDL-cholesterol concentrations to a median of 63 or 77 mg/dL, respectively, at 8 months. While a favorable trend toward reduction of major cardiovascular events was observed in this study, it is possible that more intensive therapy is required immediately after the onset of ACS during the period of greatest clinical instability to achieve a more rapid clinical benefit. However, the possible adverse effects of high dosage of statins (e.g., myopathy) should be considered when contemplating early and intensive statin therapy.

In a randomized, double-blind, active-controlled study (Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 [PROVE IT—TIMI 22]) in over 4000 patients hospitalized for ACS within the preceding 10 days, treatment with intensive antilipemic therapy (atorvastatin 80 mg daily) or standard antilipemic therapy (pravastatin 40 mg daily) for a mean of 2 years reduced LDL-cholesterol concentrations to a median of 62 or 95 mg/dL, respectively. Compared with the standard regimen, treatment with the intensive regimen resulted in a 16% reduction in the composite risk of primary end points, including a 14% reduction in the need for revascularization procedures and a 29% reduction in the risk of recurrent unstable angina. Atorvastatin therapy also was associated with reductions in the end points of death from any cause (28%) and of death or MI (18%) compared with pravastatin therapy, but these differences were not statistically significant. Results of this study suggest that among patients who have recently had an ACS, an intensive statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen, and that patients benefit from early and continued lowering of LDL-cholesterol to levels substantially below currently recommended target levels. However, the possible adverse effects of high dosage of statins (e.g., myopathy) should be considered when contemplating early and intensive statin therapy.

Findings from a large prospective, observational study (involving review of a database of over 300,000 patients hospitalized for acute MI) indicate that initiation or continuation of statins within the first 24 hours of hospitalization for an acute MI is associated with a decreased risk of in-hospital mortality compared with no statin use (4 or 5.3% for initiation or continuation of statins, respectively, compared with 15.4% for no statin therapy); discontinuation of statin therapy after hospitalization was associated with a slightly increased risk of mortality (16.5%) compared with no statin therapy (15.4%). In this study, early statin use also was associated with a lower incidence of cardiogenic shock, cardiac arrest, cardiac rupture, and ventricular tachycardia/fibrillation, but not recurrent MI. While results of this study provide strong clinical evidence to support the hypothesis of early, direct cardioprotective effects of statins in acute MI, adequately powered, prospective randomized clinical trials are needed to confirm these findings.

In a Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) substudy in patients hospitalized for acute MI or unstable angina, initiation of high-dose atorvastatin therapy (80 mg daily) in the early phase of an acute coronary event (i.e., between 24 and 96 hours following hospital admission) reduced the risk of nonfatal stroke and fatal plus nonfatal stroke by approximately 50%; effects of lower dosages of the drug on the risk of stroke have not been established. Some limitations of this study include the short duration (16 weeks) of therapy and small absolute number of cerebrovascular events (12 fatal or nonfatal strokes in the atorvastatin group and 24 in the placebo group); further study is needed to confirm the findings.

Results of a pooled analysis of randomized, controlled trials in patients with ACS indicate that, compared with moderate antilipemic therapy or placebo, early (i.e., initiated within 14 days of hospitalization for ACS) and intensive statin therapy reduced the overall incidence of cardiovascular events and cardiovascular death. The overall cardiovascular benefit began to occur between 4–12 months of therapy and was maintained during the 2 years of follow-up. However, results of this analysis should be interpreted with caution because of several limitations (e.g., statistical heterogeneity, limited number of trials, data abstracted from literature and not from individual patient data); an additional pooled analysis using data from individual patients may be needed to confirm the results of this study.

Statin Therapy Following Percutaneous Coronary Intervention

Certain statins (i.e., fluvastatin) have been shown to reduce the risk of cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). In a randomized, double-blind, placebo-controlled study (Lescol Intervention Prevention Study [LIPS]) in 1677 patients with stable or unstable angina or silent ischemia who had undergone a first percutaneous coronary intervention (PCI), therapy with fluvastatin (40 mg twice daily), initiated within a mean of 3 days following PCI and continued for a median of 3.9 years, resulted in a 22% reduction in the relative risk and a 5.3% reduction in the absolute risk of fatal or nonfatal major adverse cardiac events (e.g., cardiac death, nonfatal MI, PCI for a new lesion, or repeat PCI or coronary artery bypass grafting [CABG] procedure). Reduction in the risk of adverse cardiac events also was observed in geriatric patients (older than 65 years of age). Revascularization procedures (repeat PCI or CABG) involving the originally instrumented site comprised most of the initial recurrent adverse cardiac events; these procedures were performed in 143 or 171 patients receiving fluvastatin or placebo, respectively, within the first 6 months following the initial procedure. Treatment with fluvastatin also was associated with a 32% reduction in the risk of late revascularization procedures (i.e., PCI or CABG occurring at the original site more than 6 months following the initial procedure, or at another site).

Statins have been shown to reduce the rate of restenosis following coronary stent implantation. In a retrospective study in patients undergoing coronary stent implantation, statin therapy was associated with a substantial reduction in restenosis development (25.4% in statin-treated patients versus 38% in placebo-treated patients) during a follow-up period of 6 months. In addition, statin-treated patients also had a reduced incidence of MI and repeat revascularization procedures.

Statin Therapy in Patients with Heart Failure

Data from observational studies indicate that statins may have beneficial effects on clinical outcomes in patients with heart failure^{† [off-label]}. In one study, adult patients with heart failure who received statin therapy had a 24 or 21% lower relative risk of death or hospitalization for heart failure, respectively, compared with those who did not receive statin therapy. In another study, geriatric patients (65 years of age or older) with heart failurewho received statin therapy had a 20 or 18% reduction in mortality risk at 1 or 3 years, respectively, compared with those who did not receive statin therapy. However, randomized, controlled studies evaluating clinical outcomes (particularly in patients with nonischemic heart failure in whom antilipemic therapy is not otherwise recommended) are needed to clarify the roles of statins in the management of heart failure.

Reducing Progression of Coronary Atherosclerosis

Statins are used to slow the progression of coronary atherosclerosis. For additional details regarding the use of specific statins, see the individual statin monographs in 24:06.08.

Statin therapy has been shown to slow the progression and/or induce regression of atherosclerosis in both coronary and carotid arteries by reducing intimal-medial wall thickness (IMT). (See Antiatherogenic Effects under Pharmacology.) In numerous double-blind, placebo-controlled studies in men and women with documented CHD (e.g., atherosclerosis, angina pectoris) and normal to moderately elevated lipoprotein concentrations, progression of atherosclerosis at 2–4 years (measured as the mean per-patient changes from baseline in mean and minimal coronary artery lumen diameters, diameter stenosis, and formation of new lesions) was reduced in patients who received recommended daily dosages of a statin compared with that in those receiving placebo.

Treatment with a statin also has been shown to reduce the rate of progression of atherosclerosis in the carotid arteries. In several double-blind, placebo-controlled studies, hypercholesterolemic patients with or without CHD who received recommended daily dosages of atorvastatin, lovastatin, pravastatin, or rosuvastatin for a median of 2–3 years showed less progression of atherosclerosis (as determined by B-mode ultrasound quantification of carotid artery IMT) compared with those receiving placebo.

Results from several atherosclerosis regression trials in patients with documented CHD, including atherosclerosis and angina pectoris, and mild to moderate hypercholesterolemia indicate that treatment with statins is associated with a reduction in the incidence of clinical events (i.e., death, MI, revascularization procedures) compared with that in patients receiving placebo.

Intensive antilipemic therapy with atorvastatin has been shown to slow the progression of coronary atherosclerosis^{† [off-label]} in patients with CHD. In a randomized, double-blind, active-control study (Reversal of Atherosclerosis with Aggressive Lipid Lowering [REVERSAL]) in 654 patients with CHD, treatment with intensive antilipemic therapy (atorvastatin 80 mg daily) or moderate antilipemic therapy (pravastatin 40 mg daily) for 18 months reduced LDL-cholesterol concentrations to a mean of 79 or 110 mg/dL, respectively. Treatment with the intensive regimen was associated with a substantially lower progression rate (measured by percent change in atheroma volume) compared with treatment with the moderate regimen. Compared with baseline values, patients treated with atorvastatin had no change in atheroma burden, whereas patients treated with pravastatin showed progression of coronary atherosclerosis. In addition, concentrations of C-reactive protein were reduced by 36.4% in atorvastatin-treated patients and by 5.2% in pravastatin-treated patients. It has been suggested that the differences in atherosclerosis progression between atorvastatin and pravastatin may be related to the greater reduction in atherogenic lipoproteins and C-reactive protein concentrations in patients treated with atorvastatin.

Combination Antilipemic Therapy

The addition of a nonstatin drug to statin therapy may be considered in certain high-risk patients who require further reductions in LDL-cholesterol concentrations, particularly if there is evidence from randomized controlled studies suggesting that addition of the nonstatin drug further reduces ASCVD events. If combination therapy is considered, selection of the nonstatin drug should be based on the risk and benefit profile (i.e., reduction in ASCVD risk outweighs the drug's potential for adverse effects and drug interactions) and patient preferences. Ezetimibe is the most commonly used nonstatin agent; the drug can reduce LDL-cholesterol concentrations by 13–20% and is associated with a low incidence of adverse effects. PCSK9 inhibitors also can substantially reduce LDL cholesterol and are generally well tolerated, but long-term safety remains to be established. Although fibric acid derivatives and niacin have mild LDL-lowering effects, randomized controlled studies do not support their use as add-on drugs to statin therapy.

In the Impact on Global Health Outcomes (AIM-HIGH) study, the combination of extended-release niacin (1.5–2 g daily) and statin-based therapy (simvastatin 40–80 mg once daily, with or without ezetimibe 10 mg daily) was compared with statin-based therapy alone in patients with established cardiovascular disease (i.e., documented stable CHD, cerebrovascular or carotid disease, peripheral arterial disease). Despite a favorable effect on serum lipid concentrations (median HDL-cholesterol concentration increased from 35 to 42 mg/dL, triglyceride concentration decreased from 164 to 122 mg/dL, and LDL-cholesterol concentration decreased from 74 to 62 mg/dL), the addition of niacin to simvastatin-based therapy did not further reduce the incidence of the primary end point (i.e., composite of death from CHD, nonfatal MI, ischemic stroke, hospitalization for more than 23 hours for ACS, or symptom-driven coronary or cerebral revascularization) compared with simvastatin therapy alone over a follow-up period of 36 months. The addition of extended-release niacin to existing simvastatin therapy, however, did increase the risk of adverse effects (e.g., pruritus, flushing, adverse GI effects, increased blood glucose concentrations). The investigators of this study stated that whether such combination therapy provides incremental benefit in higher-risk patients or in those receiving suboptimal statin therapy remains to be established.

Data from another large randomized, double-blind, multicenter study involving 25,673 adults with cardiovascular disease confirmed findings of the AIM-HIGH study. In the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), the combination of extended-release niacin/laropiprant (2 g/40 mg daily) (no longer commercially available ) and statin-based therapy (simvastatin 40 mg once daily, with or without ezetimibe 10 mg daily) was compared with statin-based therapy alone in patients with established cardiovascular disease (i.e., history of MI, cerebrovascular disease, peripheral arterial disease, diabetes mellitus with evidence of symptomatic coronary disease). Despite a favorable effect on serum lipid concentrations (additional 6-mg/dL increase in HDL-cholesterol concentration, 33-mg/dL reduction in triglyceride concentration, and 10-mg/dL reduction in LDL-cholesterol concentration), the addition of niacin/laropiprant to simvastatin-based therapy did not further reduce the incidence of major cardiovascular events (i.e., nonfatal MI, death from coronary causes, stroke of any type, coronary or noncoronary revascularization) compared with simvastatin-based therapy alone over a median follow-up of 3.9 years. The addition of niacin/laropiprant to existing simvastatin-based therapy, however, did increase the risk of severe adverse effects, including disturbances in glycemic control requiring hospitalization, development of diabetes mellitus, adverse GI effects, myopathy, gout, rash, skin ulceration, and, unexpectedly, infection and bleeding. In light of these findings, some clinicians state that niacin should be reserved as a fourth-line agent (after intensive lifestyle modifications, fibric acid derivatives, and omega-3-acid ethyl esters) for patients with severe hypertriglyceridemia in whom the primary goal of treatment is prevention of pancreatitis.

Early findings from a randomized controlled study (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression [ENHANCE]) indicated that the fixed-combination preparation containing simvastatin and ezetimibe was not superior to simvastatin monotherapy in reducing carotid intimal-medial wall thickness (cIMT) in patients with heterozygous familial hypercholesterolemia despite the observed additive effects of the combination regimen on LDL cholesterol. However, a more recent study (the Improved Reduction of Outcomes: Vytorin Efficacy International trial [IMPROVE-IT]) in 18,144 post-ACS patients with baseline LDL-cholesterol concentrations of 50–125 mg/dL (or 50–100 mg/dL if they were receiving lipid-lowering therapy) demonstrated that the addition of ezetimibe (10 mg daily) to simvastatin (40 mg daily) not only achieved a 24% further reduction in LDL cholesterol concentrations, but also improved cardiovascular outcomes (a composite end point of cardiovascular death, nonfatal MI, unstable angina requiring hospitalization, coronary revascularization, or nonfatal stroke) compared with simvastatin (40 mg daily) monotherapy; the absolute risk reduction for the composite primary outcome was 2% over 7 years.

Patients with Chronic Kidney Disease

Chronic kidney disease is a risk-enhancing factor for ASCVD. Some studies have found that the cardiovascular risk in patients with chronic kidney disease may be as high as that of patients with diabetes mellitus. Several clinical studies have evaluated the potential benefits of LDL-cholesterol lowering with statins in patients with chronic kidney disease. Because clinical studies have demonstrated an absolute benefit of statin use in patients with chronic kidney disease, the 2018 AHA/ACC cholesterol management guideline states that initiation of a moderate-intensity statin or moderate-intensity statin combined with ezetimibe may be useful in adults 40–75 years of age with chronic kidney disease (not treated with dialysis or transplantation) and LDL-cholesterol concentrations of 70–189 mg/dL who have a 10-year ASCVD risk of 7.5% or higher. Initiation of statin therapy is not recommended in adults with advanced kidney disease requiring dialysis or kidney transplantation because of a lack of benefit demonstrated in randomized controlled studies with these populations; however, it may be reasonable to continue such therapy in patients who are currently receiving treatment.

In the Deutsche Diabetes Dialyse Studie (4D) in which 1255 patients with type 2 diabetes mellitus on maintenance hemodialysis received atorvastatin 20 mg daily or placebo, atorvastatin had no substantial effect on the primary composite end point of cardiovascular death, nonfatal MI, and stroke after a median follow-up of 4 years. Although atorvastatin reduced the rate of all cardiac events, a secondary end point in the study, the difference between drug and placebo was only nominally significant. Similar findings were reported with rosuvastatin in the Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis (AURORA), a randomized, double-blind study in 2776 patients undergoing hemodialysis. In this study, treatment with rosuvastatin 10 mg daily did not substantially reduce the primary composite end point of cardiovascular death, nonfatal MI, or nonfatal stroke compared with placebo. Results of another randomized, double-blind study (Assessment of Lescol in Renal Transplantation [ALERT]) in 2102 renal transplant patients showed no substantial effect of fluvastatin on the primary end point of major adverse cardiac events (defined as cardiac death, nonfatal MI, or coronary intervention procedure) compared with placebo at a mean duration of follow-up of 5.1 years, although fluvastatin appeared to reduced the risk of cardiac deaths and nonfatal MI.

Results of a large, randomized, double-blind study (Study of Heart and Renal Protection [SHARP]) in more than 9000 patients with moderate to severe chronic kidney disease and no known history of MI or coronary revascularization demonstrated that the fixed-combination preparation containing ezetimibe and simvastatin (10 and 20 mg daily, respectively) reduced major vascular and atherosclerotic events; at a median duration of follow up of 4.9 years, the risk of a major vascular event (nonfatal MI or cardiac death, stroke, or revascularization excluding dialysis access procedures) was reduced by 16% and the risk of a major atherosclerotic event (nonfatal MI or cardiac death, nonhemorrhagic stroke, or arterial revascularization excluding dialysis access procedures) was reduced by 17% in patients receiving the fixed-combination preparation compared with those receiving placebo. The treatment effect was largely driven by a substantial reduction in ischemic strokes and arterial revascularization procedures.

Dyslipidemias

Statins are used as adjuncts to nondrug therapies (e.g., dietary management) to decrease elevated serum total and LDL-cholesterol, apolipoprotein B (apo B), and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the treatment of specific dyslipidemias, including primary hypercholesterolemia or mixed dyslipidemia, homozygous familial hypercholesterolemia, primary dysbetalipoproteinemia, and hypertriglyceridemia. Statins have not been studied in conditions where the principal lipoprotein abnormality is elevated chylomicrons.

Primary Hypercholesterolemia or Mixed Dyslipidemia

Statins are used as an adjunct to nondrug therapies (e.g., dietary management) in adults to decrease elevated serum total and LDL-cholesterol, apo B, and triglyceride concentrations, and to increase serum HDL-cholesterol concentrations in the management of primary hypercholesterolemia or mixed dyslipidemia, including heterozygous familial hypercholesterolemia and other causes of hypercholesterolemia (e.g., polygenic hypercholesterolemia). Statins also are used as adjuncts to dietary therapy and lifestyle modifications in the treatment of heterozygous familial hypercholesterolemia in children who, despite an adequate trial of dietary management, have a serum LDL-cholesterol concentration of 190 mg/dL or greater or a serum LDL-cholesterol concentration of 160 mg/dL or greater and either a family history of premature cardiovascular disease or 2 or more other risk factors. Statins also are used in combination with fenofibric acid to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD (or CHD risk equivalents) who are receiving optimal statin therapy; however, no additional benefit on cardiovascular morbidity and mortality has been demonstrated with such combination therapy beyond that already established with statin monotherapy. (See Patients with Diabetes Mellitus under Uses.)

Reductions in total and LDL-cholesterol concentrations produced by usual dosages of statins substantially exceed those achieved with placebo. Mean reductions of 16–46% in total cholesterol concentration, 21–63% in LDL-cholesterol concentration, 18–54% in apo B concentration, and 6–37% in triglyceride concentration have been reported in controlled and uncontrolled studies in patients with primary hypercholesterolemia who received recommended daily dosages of a statin for at least 6 weeks. Modest and variable increases in HDL-cholesterol concentrations (2–16%) also were observed in patients receiving statin therapy.

Data from comparative studies suggest that reductions in total and LDL-cholesterol concentrations produced by statins generally equal or exceed those produced by other antilipemic agents (e.g., bile acid sequestrants, niacin, fibric acid derivatives). Pooled data from several placebo-controlled studies comparing 12–24 weeks of statin therapy (40–80 mg of pravastatin or 20–40 mg of simvastatin daily) with that of cholestyramine (8–24 g daily in divided doses) in patients with primary hypercholesterolemia indicate that statins may be equally or more effective than cholestyramine in reducing total cholesterol (25–36% for pravastatin or simvastatin versus 15–23% for cholestyramine) and LDL-cholesterol concentrations (31–43 versus 21–32%). Statins also were found to be more effective than cholestyramine in improving triglyceride concentrations, as evidenced by 13–21% reductions in statin-treated patients versus 11–21% increases in cholestyramine-treated patients.

Statin therapy has been shown to be superior to niacin in reducing total and LDL-cholesterol concentrations but less effective in reducing triglyceride and increasing HDL-cholesterol concentrations. In a multicenter, randomized, placebo-controlled, comparative study in patients with primary types IIa and IIb hyperlipoproteinemia, treatment with pravastatin (40 mg daily) for 8 weeks was associated with 23 and 33% reductions in total and LDL-cholesterol concentrations, respectively, compared with 11 and 16% reductions, respectively, achieved with niacin therapy (0.5–1 g twice daily). Although results of this study indicate no substantial difference between pravastatin and niacin in improving triglyceride and HDL-cholesterol concentrations, evidence from a randomized, crossover, comparative trial in a limited number of patients with combined hyperlipidemia suggests that niacin may more effective than pravastatin in improving these lipid parameters. Treatment with niacin (1.5 g 3 times daily) for 8 weeks resulted in a 32% reduction in triglycerides and a 27% increase in HDL-cholesterol concentrations, while treatment with pravastatin (40 mg daily) produced only modest improvements in these lipid parameters (-4 and +3%, respectively).

Statins have been shown to be superior to fibric acid derivatives in lowering total and LDL-cholesterol concentrations but less effective in improving triglyceride and HDL-cholesterol concentrations. In 2 randomized studies comparing therapy with pravastatin (40 mg daily) with that of gemfibrozil (600 mg twice daily) for 12–24 weeks in patients with primary hypercholesterolemia, pravastatin was more effective in reducing total cholesterol (23–26% for pravastatin versus 14–15% for gemfibrozil) and LDL-cholesterol (30–34% versus 16–17%); however, the drug was less effective than gemfibrozil in reducing triglyceride (5–14% versus 37–42%) and raising HDL-cholesterol concentrations (5–6% versus 13–15%).

Combined use of a statin and other antilipemic agents (e.g., bile acid sequestrants, niacin, fibric acid derivatives, ezetimibe) produces additive antilipemic effects and, in some cases, can also result in additional cardiovascular benefits. (See Combination Antilipemic Therapy under Uses.) The addition of a bile acid sequestrant to statin therapy further reduces LDL-cholesterol by an additional 3–20%. The addition of ezetimibe (10 mg daily) to statin therapy reduces LDL-cholesterol by an additional 25% compared with a 4% reduction following addition of placebo. Combining niacin (1–3 g daily) with various statins (e.g., fluvastatin, pravastatin) for 8–18 weeks in hypercholesterolemic patients with or without coronary artery disease further reduced total cholesterol, LDL-cholesterol, apo B, and triglyceride concentrations by an additional 9–12, 9–19, 11%, and 18–27%, respectively, and increased HDL-cholesterol and apo A concentrations by an additional 3–29 and 11%, respectively. Combining a fibric acid derivative (e.g., fenofibrate, gemfibrozil) with statin therapy (e.g., pravastatin, simvastatin) in patients with primary hypercholesterolemia further reduced triglyceride concentrations by an additional 28–32% and increased HDL-cholesterol concentrations by an additional 7–12%.

The benefits of combined use of a statin and other lipid-lowering drugs should be weighed against the potential risks of hepatotoxicity, myopathy, and rhabdomyolysis; it should be noted that the addition of fenofibrate or niacin to existing statin-based therapy has not been shown to further reduce the incidence of major cardiovascular events in patients with diabetes mellitus or established cardiovascular disease, respectively, compared with statin-based therapy alone.

Homozygous Familial Hypercholesterolemia

Statins are used alone or in combination with other lipid-lowering treatments (e.g., LDL apheresis) to reduce total cholesterol, LDL-cholesterol, and apo B concentrations in patients with homozygous familial hypercholesterolemia. Patients with homozygous familial hypercholesterolemia usually respond poorly to combined dietary management and drug therapy, including regimens containing a statin, in part because these patients have poorly functioning, few, or no LDL receptors.

Data concerning the effectiveness of statins in the management of homozygous familial hypercholesterolemia are limited. In several small controlled and uncontrolled studies, 86–92% of patients with homozygous familial hypercholesterolemia who received atorvastatin (20–80 mg daily) or simvastatin (40–80 mg daily) had marked reductions in LDL-cholesterol concentrations (7–53%) while 8–14% of patients showed increases (7–24%) in this lipoprotein fraction. In an open-label study, reductions in LDL-cholesterol concentrations achieved with usual dosages of rosuvastatin (20–40 mg daily) reportedly averaged 22%. In a randomized placebo-controlled study in 14 children and adolescents 7 years of age or older with homozygous familial hypercholesterolemia, rosuvastatin (20 mg daily) reduced LDL-cholesterol concentrations by approximately 22%, total cholesterol by approximately 20%, non-HDL-cholesterol by approximately 23%, and apo B by approximately 17%. In another small, open-label study in patients with homozygous familial hypercholesterolemia undergoing plasma exchange or LDL-apheresis, treatment with atorvastatin (80 mg daily) for 8 weeks further reduced LDL-cholesterol concentrations by approximately 31% during pre- and post-apheresis. The addition of ezetimibe (10 mg daily) to atorvastatin or simvastatin therapy (40 or 80 mg daily) further reduced LDL-cholesterol concentrations by an additional 21%.

Primary Dysbetalipoproteinemia

Statins are used as adjuncts to nondrug therapies (e.g., dietary management) for the treatment of primary dysbetalipoproteinemia in patients who do not respond adequately to diet.

In several small double-blind, crossover studies in a limited number of patients with primary dysbetalipoproteinemia who received recommended daily dosages of a statin (e.g., pravastatin, rosuvastatin, simvastatin), total cholesterol, triglyceride, and non-HDL-cholesterol concentrations decreased by 31–58, 12–53, and 36–64%, respectively.

Hypertriglyceridemia

Statins are used as adjuncts to nondrug therapies (e.g., dietary management) in the treatment of elevated serum triglyceride concentrations.

Mean reductions in total cholesterol concentrations of 22–44%, LDL-cholesterol concentrations of 27–45%, VLDL-cholesterol concentrations of 25–62%, triglyceride concentrations of 21–52%, and non-HDL-cholesterol concentrations of 27–52% have been reported in patients with hypertriglyceridemia who received recommended daily dosages of a statin (e.g., atorvastatin, pravastatin, rosuvastatin, simvastatin). Modest increases in HDL-cholesterol concentrations (3–22%) also were observed in patients receiving statin therapy.

An analysis of pooled data from a number of studies in which statins were used suggests that these agents are effective in decreasing triglyceride concentrations principally in patients with hypertriglyceridemia (baseline concentrations exceeding 250 mg/dL); in this analysis, such benefit was not observed in those with baseline triglyceride concentrations below 150 mg/dL. In addition, limited evidence suggests that the relative potency of a statin in reducing triglyceride concentrations may be related to its efficacy in reducing LDL-cholesterol concentrations.

Secondary Dyslipidemias

Some statins have been used to reduce total and LDL-cholesterol concentrations in a limited number of patients with hypercholesterolemia associated with chronic renal insufficiency^{† [off-label]}, cardiac^{† [off-label]} or renal^{† [off-label]} transplantation, or nephrotic syndrome^†. Additional studies are necessary to determine the role, if any, of statins in patients with these disorders.

Other Uses

Limited data indicate that use of statins may be associated with an increase in bone mass density^†; however, results of epidemiologic studies evaluating the effect of statins on risk of fractures^† have been conflicting. Results of an observational study indicate a lower prevalence of Alzheimer’s disease^† among patients who received certain statins (i.e., lovastatin, pravastatin). Further study is needed to establish the usefulness of statins in these conditions.

HMG-CoA Reductase Inhibitors General Statement Dosage and Administration

Administration

All statins are administered orally once daily. While the manufacturers of some statins state that these drugs may be taken without regard to time of day, some evidence suggests that statins should be administered in the evening or at bedtime for optimal efficacy in lowering LDL cholesterol since the rate of hepatic cholesterol synthesis is greatest at night. Most statins may be administered without regard to meals; however, the manufacturer of lovastatin states that the drug should be given with the evening meal for optimal absorption.

Antilipemic therapy is an adjunct to, not a substitute for, lifestyle modification therapies that reduce the risk of atherosclerotic cardiovascular disease (ASCVD). Adherence to lifestyle modification for ASCVD risk reduction in addition to statin therapy should be reinforced periodically.

The American Heart Association (AHA)/American College of Cardiology (ACC) guideline for the management of high blood cholesterol recommends that lipoprotein concentrations be monitored within 4–12 weeks following initiation of statin therapy or after dosage adjustments (to determine the patient’s response to therapy and adherence) and then every 3–12 months thereafter as clinically indicated.

Dosage

Dosage of statins must be carefully adjusted according to individual requirements and response. The AHA/ACC cholesterol management guideline states that the appropriate intensity of statin therapy should be used to reduce ASCVD risk. The guideline recommends use of high-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 50% or more); if high-intensity statin therapy is not possible (e.g., because of a contraindication or intolerable adverse effect), moderate-intensity statin therapy (defined as reducing LDL-cholesterol concentrations by 30–49%) should be used.

Because the risk of myopathy is dose related, AHA/ACC and the National Heart, Lung and Blood Institute (NHLBI) clinical advisory panel on statins state that statin dosages generally should not exceed those required to attain the desired percent reduction in LDL-cholesterol concentration. The manufacturer of simvastatin states that the 80-mg dose of the drug should be restricted to patients who have been receiving long-term therapy (e.g., 12 months or longer) at this dosage without evidence of muscle toxicity. Dosage should be increased at intervals of no less than 4 weeks until the desired effect on lipoprotein concentrations is observed; reduction of statin dosage can be considered in patients whose serum cholesterol concentrations fall below the desired target range.

Concomitant use of statins with certain other drugs may increase the risk of myopathy and may require dosage adjustments or dosage limitations.

Dosage in Renal and Hepatic Impairment

Since most statins (e.g., atorvastatin, fluvastatin, lovastatin, rosuvastatin, simvastatin) do not undergo substantial renal excretion, the manufacturers state that modification of dosage should not be necessary in patients with mild renal impairment (creatinine clearance of 61–90 mL/minute per 1.73 m²). However, pitavastatin and pravastatin undergo renal and hepatic elimination, with renal excretion reaching 15 and 20–47% of the administered dose, respectively. (See Elimination under Pharmacokinetics.) Because the possibility of accumulation of pravastatin and other statins cannot be ruled out, these drugs should be administered with caution in patients with moderate to severe renal impairment (creatinine clearance less than 60 mL/minute per 1.73 m²), initiating therapy with the drug under close monitoring and at reduced daily dosages.

Since statins are partially metabolized in the liver and potentially may accumulate in the plasma of patients with hepatic impairment, these drugs should be used with caution in patients who consume substantial amounts of alcohol and/or who have a history of liver disease; such patients should be monitored closely while receiving statin therapy. Statins are contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase concentrations.

Cautions for HMG-CoA Reductase Inhibitors General Statement

At usual dosages, statins usually are well tolerated and are associated with a low incidence of adverse effects. Adverse effects reported in the Cautions section include those reported in clinical trials and during postmarketing studies, and a causal relationship to statin therapy has not necessarily been established.

Adverse effects reported with statin therapy usually have been mild and transient and similar in incidence to placebo. The most common adverse effects observed with statin therapy in controlled studies were GI disturbances, fatigue, localized pain, and headache. In controlled clinical trials, 0.3–4.6% of patients receiving statins discontinued the drugs because of adverse effects. Adverse effects most frequently resulting in drug discontinuance in long-term clinical studies were rash, musculoskeletal pain, asymptomatic increases in serum aminotransferase concentrations, and mild, nonspecific GI disturbances. No overall differences in the adverse effect profile were observed between geriatric and younger patients.

Hepatic Effects

Increases in serum aminotransferase (transaminase) concentrations (i.e., AST [SGOT], ALT [SGPT]), including to more than 3 times the upper limit of normal, have been reported in patients receiving statins. (See Precautions and Contraindications under Cautions.) Increases in serum aminotransferase concentrations generally are dose dependent, are not related to the LDL-cholesterol reduction, and have not been associated with jaundice or cholestasis, although at least one patient in clinical trials developed jaundice. Increases in ALT and/or AST to more than 3 times the upper limit of normal most often are transient and will resolve spontaneously in 70% of patients even if the statin and original dosage are continued unchanged; following reduction of dosage or interruption or discontinuance of statin therapy, serum aminotransferase concentrations usually return slowly to pretreatment values without adverse sequelae. Increases in serum aminotransferase concentrations usually do not recur following rechallenge with the same statin or selection of another statin. Cases of fatal and nonfatal hepatic failure have been reported rarely in patients receiving statins during postmarketing surveillance. Pancreatitis, hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty liver changes, biliary pain, increased serum alkaline phosphatase concentrations, increased serum γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP) concentrations, increased serum bilirubin concentrations, cirrhosis, fulminant hepatic necrosis, and hepatoma also have been reported with statin therapy.

Musculoskeletal Effects

Uncomplicated myalgia (characterized by muscle pain or weakness) is the most common adverse musculoskeletal effect of statins, occurring in approximately 1–6% of patients receiving the drugs in controlled clinical trials, Arthralgia occurred in about 1–5% of patients receiving statins in controlled clinical trials. Increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations, muscle cramps, leg cramps, back pain, shoulder pain, arthritis, and myositis, also have been reported with statin therapy. Bursitis, tenosynovitis, arthropathy, myasthenia, tendinous contracture, tendon rupture, tendon disorder, and polymyositis also have been reported with some statins.

Myopathy (manifested as muscle pain, tenderness, soreness, weakness, and/or cramps plus serum CK concentration increases exceeding 10 times the upper limit of normal) occurred in less than 0.7% of patients receiving statins in clinical trials. Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has been reported rarely in patients receiving statins. The risk of myopathy appears to be increased in patients receiving higher dosages of statins, patients with multisystem disease (e.g., renal [particularly with pravastatin] or hepatic impairment), patients with concurrent serious infections or uncontrolled hypothyroidism, geriatric patients (65 years of age and older), women, patients with small body frame and frailty, and patients undergoing surgery (i.e., during perioperative periods). The risk of myopathy and/or rhabdomyolysis also is increased with concomitant use of statins and certain drugs or foods (e.g., cyclosporine, niacin, fibric acid derivatives, macrolide antibiotics [e.g., erythromycin, clarithromycin], certain azole antifungals [i.e., itraconazole, ketoconazole, posaconazole, voriconazole], alcohol, HIV protease inhibitors, nefazodone, amiodarone, cobicistat-containing preparations, dronedarone, amlodipine, verapamil, diltiazem, danazol, colchicine, ranolazine, lomitapide, simeprevir, grapefruit juice). (See Drug Interactions.)

Rhabdomyolysis (characterized by muscle pain or weakness with marked increases [exceeding 10 times the upper limit of normal] in serum CK concentrations and increases in serum creatinine concentrations [usually accompanied by brown urine and urinary myoglobinuria]) with or without acute renal failure secondary to myoglobinuria has occurred rarely with all statins. Fatalities secondary to rhabdomyolysis also have been reported in patients receiving statin therapy. As of June 2001, fatal rhabdomyolysis was reported in 6, 31, 0, 19, 3, or 14 of patients receiving atorvastatin, cerivastatin (no longer commercially available in the US), fluvastatin, lovastatin, pravastatin, or simvastatin, respectively. Among the 31 cases of fatal rhabdomyolysis associated with cerivastatin, 12 occurred with concomitant gemfibrozil therapy (see Fibric Acid Derivatives under Drug Interactions), while another 12 occurred following administration of a higher initial dosage (0.8 mg daily) of the drug (as monotherapy); fatal rhabdomyolysis associated with cerivastatin also appears to occur more frequently in geriatric patients. (See Geriatric Precautions under Cautions.) Based on available data, the reporting rate (calculated as the number of reported cases divided by the total number of prescriptions dispensed since initial marketing of the drug to May 2001) of fatal rhabdomyolysis associated with atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, or simvastatin monotherapy is 0.04, 1.9, 0, 0.19, 0.04, or 0.12 per million prescriptions, respectively. In view of a substantially higher reporting rate of fatal rhabdomyolysis associated with cerivastatin (10–50 times higher than that for other statins), the manufacturer (Bayer) announced a voluntary withdrawal of the drug from the world market in August 2001.

FDA notes that the data on severe or fatal rhabdomyolysis represent reporting rates, not incidence rates, and that statistically rigorous comparisons between drugs are not recommended. However, the American College of Cardiology (ACC), the American Heart Association (AHA), and the National Heart, Lung and Blood Institute (NHLBI) clinical advisory panel on statins state that there appears to be no clinically important differences in the reporting rate of fatal rhabdomyolysis among atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin, and that clinicians should consider the rates of severe myopathy equivalent among all of these statins. The risk of severe adverse musculoskeletal effects associated with rosuvastatin appears to be similar to that with other statins.

Any patient taking a statin with or without gemfibrozil who experiences muscle pain, tenderness (especially in the calves or lower back), or weakness; brown urine; flu-like symptoms; and malaise should consult a clinician immediately. (See Precautions and Contraindications under Cautions.) However, it should be noted that myopathy or rhabdomyolysis also has occurred in the absence of such manifestations of muscle injury.

GI Effects

The most frequent adverse GI effects of statins are diarrhea, abdominal pain, flatulence, nausea and/or vomiting, constipation, dyspepsia, and heartburn, which occurred in approximately 1–7% of patients receiving a statin in controlled clinical trials. Anorexia also has been reported with statin therapy. Other adverse GI effects reported with at least one statin include increased or decreased appetite, dysphagia, cheilitis, dry mouth, stomatitis, mouth ulceration, gum hemorrhage, glossitis, tooth disorder esophagitis, eructation, acid regurgitation, gastritis, GI hemorrhage, gastroenteritis, stomach ulcer, enteritis, duodenal ulcer, colitis, rectal hemorrhage, tenesmus, and melena.

Respiratory Effects

Upper respiratory tract infection occurred in about 1–16% of patients receiving statins in controlled clinical trials. Pharyngitis, rhinitis, sinusitis, bronchitis, and cough, occurred in approximately 3–13, 1–11 , 2–7, 2, and 1–2%, respectively, of patients receiving various statins in controlled clinical trials. Pneumonia, asthma, epistaxis, and interstitial lung disease also have been reported with some statins.

Dermatologic and Sensitivity Reactions

Rash is the most common dermatologic reaction of statins, occurring in about 1–4% of patients receiving the drugs in controlled clinical trials. Alopecia, pruritus, and skin changes (e.g., nodules, discoloration, dry skin and mucous membranes, changes to hair and nails) also have been reported with statins. Sweating, acne, eczema, seborrhea, phlebitis, and skin ulcer have been reported with at least one statin.

Hypersensitivity reactions have occurred rarely with statin therapy during clinical trials or postmarketing surveillance. Such reactions may include anaphylaxis, angioedema, head/neck edema, contact dermatitis, lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive antinuclear antibody (ANA) titer, increased erythrocyte sedimentation rate, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson syndrome.

Nervous System Effects

Headache is the most frequent adverse nervous system effect of statins, occurring in about 2–17% of patients receiving the drugs in controlled clinical trials. Asthenia, fatigue, and dizziness occurred in about 1–4% of patients receiving statin therapy in controlled clinical trials. Dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, and facial paresis), tremor, hypertonia, vertigo, paresthesia, peripheral neuropathy, peripheral nerve palsy, anxiety, insomnia, somnolence, and depression also have been reported with statin therapy. Psychic disturbances, sleep disturbances, abnormal dreams, nightmares, torticollis, hypesthesia, hyperkinesia, incoordination, paralysis, neck rigidity, migraine, emotional lability, and amnesia have been reported with at least one statin.

Cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) has been reported rarely with all statins during postmarketing surveillance. This adverse CNS effect generally was nonserious and reversible, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks following discontinuance of statin therapy). Following review of available data (i.e., from the Adverse Event Reporting System [AERS] database, randomized clinical trials, observational studies, case reports), FDA concluded that cases of cognitive impairment did not appear to be associated with fixed or progressive dementia (e.g., Alzheimer’s disease) or result in clinically important cognitive decline. Development of cognitive impairment did not appear to be associated with any specific statin, age of the patient, statin dosage, or concomitant drug therapy. Therefore, FDA continues to believe that the cardiovascular benefits of statins outweigh this small increased risk of cognitive impairment. The National Lipid Association (NLA) statin safety assessment task force recommends that patients experiencing manifestations consistent with cognitive impairment be evaluated and managed appropriately.

Although peripheral neuropathy has been reported with statin therapy, the NLA statin safety assessment task force states that the potential risk of developing peripheral neuropathy during statin therapy is very small, if it exists at all. Nevertheless, the task force recommends that patients experiencing manifestations consistent with peripheral neuropathy be evaluated and managed appropriately. (See CNS Effects under Cautions.)

Ocular Effects

Because of experience with a previously studied inhibitor of cholesterol synthesis (i.e., triparanol, MER-29), the cataractogenic potential of statins has been closely monitored during clinical studies. Unlike triparanol, however, statins affect an earlier step in the cholesterol biosynthetic pathway that does not appear to result in accumulation of potentially toxic intermediate sterols (e.g., desmosterol). However, concern remains that statin-induced inhibition of cholesterol synthesis could potentially adversely affect the lens since the lens may be completely dependent on de novo cholesterol synthesis for ongoing membranal synthetic processes.

Progression of cataracts (including lens opacities) has been reported in patients receiving statins. However, data from several controlled studies in patients receiving lovastatin or simvastatin for up to 3 years indicate that the incidence of lens opacity is similar to that reported in placebo-treated patients and increases at a rate consistent with that expected as a result of normal aging. Ophthalmoplegia, blurred vision, visual disturbance (e.g., diplopia), ocular irritation, glaucoma, ocular hemorrhage, amblyopia, refraction disorder, and dry eyes have been reported with at least one statin.

Cardiovascular Effects

Adverse cardiovascular effects reported in patients receiving statin therapy include chest pain, hypertension, and angina pectoris. Palpitation, vasodilation, syncope, postural hypotension, peripheral edema, and arrhythmia have been reported with at least one statin.

Genitourinary Effects

Genitourinary system abnormalities reported in patients receiving statin therapy include change or loss of libido, sexual dysfunction, and erectile dysfunction. Impotence, epididymitis, abnormal ejaculation, vaginal hemorrhage, uterine hemorrhage, metrorrhagia, fibrocystic breast, urinary tract infection, urinary abnormality (e.g., dysuria, frequency, nocturia), cystitis, hematuria, proteinuria, renal calculus, nocturia, albuminuria, nephritis, urinary incontinence, urinary retention, and urinary urgency have been reported with at least one statin.

Dipstick-positive proteinuria and microscopic hematuria reportedly occurred more frequently in patients receiving rosuvastatin 40 mg compared with lower doses of rosuvastatin or comparator statins in clinical trials. In an analysis of available data, the FDA concluded that proteinuria in patients receiving statins is not associated with renal impairment or renal failure. Nevertheless, the NLA statin safety assessment task force recommends that patients experiencing adverse renal effects (including proteinuria) be evaluated and managed appropriately. (See Renal Effects under Cautions: Precautions and Contraindications.)

Endocrine Effects

Increases in glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) and fasting serum glucose concentrations that in some cases may exceed the threshold for the diagnosis of diabetes mellitus have been reported in patients receiving statins. Data from clinical trials and meta-analyses indicate that statin therapy may increase the risk of developing diabetes mellitus. Despite these findings, FDA continues to believe that the cardiovascular benefits of statins outweigh these small increased risks. (See Endocrine Effects under Cautions: Precautions and Contraindications.)

Other Adverse Effects

Other adverse effects reported in patients receiving statins include accidental injury, gynecomastia, and flu-like syndrome. Gout, weight gain, ecchymosis, anemia, lymphadenopathy, petechia, tinnitus, deafness, parosmia, taste loss, and taste perversion have been reported with at least one statin.

Precautions and Contraindications

General Precautions and Contraindications

Prior to institution of antilipemic therapy with statins, a vigorous attempt should be made to control serum cholesterol by appropriate dietary regimens, weight reduction, exercise, and treatment of any underlying disorder that might be the cause of lipid abnormality. The AHA/ACC guideline for the management of high blood cholesterol recommends that lipoprotein concentrations be monitored within 4–12 weeks following initiation of statin therapy and after dosage adjustments (to determine the patient’s response to therapy and adherence) and then every 3–12 months thereafter as clinically indicated. Statin dosages generally should not exceed those required to attain the desired percent reduction in LDL-cholesterol concentration, and reduction in dosage should be considered in patients whose cholesterol concentrations fall below the desired target range.

Statins are contraindicated in patients with hypersensitivity to any component of the drug formulations. These drugs also are contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases.

Hepatic Effects

The manufacturers state that liver function tests should be performed prior to initiation of statin therapy and repeated as clinically indicated (e.g., presence of manifestations suggestive of liver damage ). Although the manufacturers previously recommended more frequent monitoring of liver function, FDA concluded that serious statin-related liver injury is rare and unpredictable in individual patients, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury. The AHA/ACC cholesterol management guideline states that, during statin therapy, it is reasonable to obtain liver function tests in adults experiencing symptoms of hepatotoxicity (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, yellowing of the skin or sclera); however, routine monitoring is not recommended given the unlikely impact on clinical outcomes and lack of established cost effectiveness.

If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, the manufacturers state that statin therapy should be promptly interrupted. If an alternate etiology is not found, statin therapy should not be restarted. Patients receiving statin therapy should be advised to promptly report any symptoms suggestive of liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).

Statins should be used with caution in patients who consume substantial amounts of alcohol or in patients who have a history of liver disease; such patients should be closely monitored. The NLA expert liver panel states that patients with chronic liver disease, nonalcoholic fatty liver disease, or nonalcoholic steatohepatitis may safely receive statin therapy. Statins are contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase concentrations.

Musculoskeletal Effects

Severe or fatal rhabdomyolysis has occurred rarely with all statins. (See Cautions: Musculoskeletal Effects.) Therefore, some experts recommend that baseline serum CK concentrations be performed prior to initiation of statin therapy, particularly in patients at high risk of developing musculoskeletal toxicity (e.g., patients with personal or family history of statin intolerance or muscle disease, geriatric patients, black men, patients receiving concomitant therapy with myotoxic drugs) to aid in the diagnosis of myopathy in patients who later present with adverse musculoskeletal effects; however, routine laboratory monitoring of serum CK concentrations in the absence of clinical manifestations is not recommended given the unlikely impact on clinical outcomes and lack of established cost effectiveness. During statin therapy, it is reasonable to measure CK concentrations in adults experiencing muscle symptoms (e.g., pain, tenderness, stiffness, cramping, weakness, generalized fatigue).

An NHLBI-appointed expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents states that baseline CK concentrations should be obtained before initiating statin therapy in pediatric patients. In addition, routine monitoring for muscle toxicity is strongly recommended in children and adolescents receiving statin therapy.

Patients receiving statin therapy should be advised to report promptly any unexplained muscle pain, tenderness, weakness, or other symptoms suggestive of a possible myopathy, especially if these symptoms are accompanied by malaise or fever. The ACC, AHA, NLA statin safety assessment task force, and other experts recommend that serum CK concentrations be obtained and compared to baseline concentrations in any patient presenting with musculoskeletal symptoms suggestive of myopathy (e.g., pain, tenderness, stiffness, cramping, weakness, generalized fatigue). Because hypothyroidism may be a predisposing factor for the development of myopathy, thyrotropin (thyroid-stimulating hormone, TSH) concentrations also should be obtained in such patients. Prior to diagnosis of myopathy, common causes of musculoskeletal symptoms (e.g., exercise, strenuous work, trauma, falls, accidents, seizure, shaking chills, hypothyroidism, infections, carbon monoxide poisoning, polymyositis, dermatomyositis, alcohol abuse, drug [cocaine, amphetamines, heroin, or phencyclidine hydrochloride] abuse) should be ruled out; patients who experience musculoskeletal symptoms should be advised to minimize strenuous activities during combination therapy.

Myopathy should be considered in any patient receiving statin therapy who has diffuse myalgias, muscle tenderness or weakness, and/or marked (greater than 10 times the upper limit of normal) elevation of serum CK concentration. Statin therapy should be discontinued if serum CK concentrations become markedly elevated or if myopathy is diagnosed or suspected. The NLA statin safety assessment task force states that once musculoskeletal manifestations resolve, the same or different statin (at the same or lower dosage) may be restarted to determine the reproducibility of manifestations; recurrence of manifestations with multiple statins and dosages requires initiation of other antilipemic therapy. If myalgia (muscle pain, tenderness) is present with either no CK elevation or a moderate elevation (3–10 times the upper limit of normal), some experts recommend that patients be monitored weekly until manifestations improve; statin therapy should be discontinued if manifestations worsen. In patients with muscle discomfort and/or weakness in the presence of progressive elevations of CK concentrations on serial measurements, either a reduction in statin dosage or temporary discontinuance of therapy may be prudent; a decision can then be made whether or when to reinstitute statin therapy. Statin therapy should be withheld temporarily in any patient experiencing an acute or serious condition suggestive of myopathy or predisposing to the development of acute renal failure secondary to rhabdomyolysis (e.g., sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; uncontrolled seizures). The NLA statin safety assessment task force states that IV hydration therapy in a hospital setting should be instituted if needed in patients experiencing rhabdomyolysis; once manifestations resolve, the risks and benefits of statin therapy should be carefully reconsidered.

Because the risk of myopathy appears to be increased in geriatric patients (65 years of age and older), women, patients with small body frame and frailty, and patients with multisystem disease (e.g., chronic renal insufficiency [especially secondary to diabetes mellitus], uncontrolled hypothyroidism), statin therapy should be used with caution in such patients.

The manufacturers state that concomitant use of statins and gemfibrozil is contraindicated or should be avoided, and caution is advised when statins are used concomitantly with other fibric acid derivatives (e.g., fenofibrate). (See Drug Interactions.)

Since statins may produce elevations in serum CK and aminotransferase concentrations, this should be considered in the differential diagnosis of patients receiving statin therapy who are being evaluated for chest pain.

Endocrine Effects

Increases in HbA_1c and fasting serum glucose concentrations have been reported in patients receiving statins. (See Cautions: Endocrine Effects.) The AHA/ACC cholesterol management guideline states that patients receiving statin therapy should be evaluated for new-onset diabetes mellitus; because the benefits of statin therapy outweigh the risks of new-onset diabetes, the possibility of this adverse effect should not be a contraindication to statin therapy or a reason for discontinuance of therapy.

Statins interfere with cholesterol synthesis and lower circulating cholesterol concentrations and therefore theoretically may blunt adrenal or gonadal steroid hormone production. However, clinical studies have shown that statins do not decrease basal plasma cortisol concentration or impair adrenal reserve. Certain statins (e.g., fluvastatin, pravastatin) have been shown to decrease plasma testosterone response to human chorionic gonadotropin. The effects of statins on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects on the pituitary-gonadal axis in premenopausal females, if any, are unknown.

The manufacturers recommend that patients receiving statins who exhibit clinical evidence of endocrine dysfunction be evaluated appropriately. Caution should be used when administering a statin or another agent used to lower cholesterol concentrations concomitantly to patients also receiving other drugs (e.g., spironolactone, cimetidine) that may decrease the concentrations or activity of endogenous steroid hormones.

Renal Effects

The NLA statin safety assessment task force recommends that renal function tests be performed prior to initiating statin therapy; however, routine monitoring of serum creatinine concentrations and proteinuria for the purpose of identifying adverse renal effects is not necessary. If serum creatine concentration is elevated in the absence of rhabdomyolysis, the task force states that statin therapy may be continued; however, per labeling recommendations, dosage adjustment may be required for some statins. If unexpected proteinuria develops, the etiology should be determined; although statin therapy may be continued in patients who developed proteinuria, the task force states that dosage adjustment may be required per labeling recommendations. Although the clinical importance of proteinuria and hematuria associated with rosuvastatin is not known, the manufacturer of rosuvastatin states that dosage reduction should be considered in patients receiving the drug who have unexplained persistent proteinuria and/or hematuria during routine urinalysis testing. (See Genitourinary Effects under Cautions.) The task force states that chronic renal disease does not preclude the use of statins; however, the dosage of some statins should be adjusted in those with moderate or severe renal impairment. (See Dosage in Renal and Hepatic Impairment under Dosage and Administration.)

CNS Effects

CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, and perivascular fibrin deposits and necrosis of small vessels have been observed in animals receiving statins at various dosages (producing plasma drug concentrations approximately 14–59 times higher than the mean serum drug concentration in humans receiving recommended dosages).

The NLA statin safety assessment task force states that routine neurologic monitoring for the purpose of identifying peripheral neuropathy or impaired cognition is not recommended. Patients experiencing manifestations consistent with peripheral neuropathy should be evaluated to rule out secondary causes (e.g., diabetes mellitus, renal impairment, alcohol abuse, vitamin B₁₂ deficiency, cancer, hypothyroidism, acquired immunodeficiency syndrome [AIDS], Lyme disease, heavy metal intoxication). If a secondary cause is not identified, the task force recommends that statin therapy be discontinued for 3–6 months. If neurologic manifestations improve over this period without statin therapy, a presumptive diagnosis of statin-induced peripheral neuropathy may be made; however, because of the proven benefit of statin therapy, reinitiation of statin therapy (i.e., with a different statin and dosage) should be considered. If neurologic manifestations do not improve during the period of discontinuance, statin therapy should be reinitiated, taking into consideration the risks and benefits of such therapy. The NLA task force states that patients experiencing manifestations consistent with impaired cognition should be evaluated and managed in a similar manner as those experiencing peripheral neuropathy. These patients should first be evaluated to rule out secondary causes. If a secondary cause is not identified, statin therapy should be discontinued for 1–3 months. If cognitive impairment is not improved during this period of discontinuance, statin therapy should be reinitiated, taking into consideration the risks and benefits of such therapy. FDA continues to believe that the cardiovascular benefits of statins outweigh the small increased risk of cognitive impairment. (See Cautions: Nervous System Effects.) The ACC/AHA cholesterol management guideline states that, in patients presenting with confusion or memory impairment, it is reasonable to evaluate the patient for statin as well as nonstatin causes (e.g., exposure to other drugs, systemic or neuropsychiatric causes).

Ocular Effects

Dose-dependent increases in optic nerve degeneration were observed in animals receiving certain statins (e.g., lovastatin, simvastatin) at dosages which produced mean plasma drug concentrations approximately 12–30 times higher than the mean plasma drug concentrations observed in humans receiving the highest recommended dosages. Vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis also were observed in animals receiving certain statins (e.g., lovastatin, simvastatin) at dosages which produced mean plasma drug concentrations approximately 30 times higher than the mean plasma drug concentrations observed in humans receiving the highest recommended dosages.

Neuromuscular Effects

Use of statins does not appear to increase the risk of developing amyotrophic lateral sclerosis (ALS, Lou Gehrig disease). According to FDA analysis of data from 41 long-term (6 months to 5 years) controlled clinical trials of 7 statins (atorvastatin, cerivastatin [no longer commercially available in the US], fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), ALS was diagnosed in 9 of approximately 64,000 patients receiving statin therapy and in 10 of approximately 56,000 patients receiving placebo. The incidence of ALS was 4.2 cases per 100,000 patient-years in patients receiving statin therapy and 5 cases per 100,000 patient-years in those receiving placebo. Because of the extensive use of statins and the serious nature of ALS, FDA states that continued evaluation of the effects of statin therapy on ALS is warranted.

Pediatric Precautions

Results of several randomized, double-blind, placebo-controlled studies in children 8 years of age and older receiving pravastatin (20–40 mg daily for 2 years) or 10 years of age and older (postmenarchal girls) receiving atorvastatin (10–20 mg daily for 26 weeks), lovastatin (10–40 mg daily for at least 24 weeks), rosuvastatin (5–20 mg daily for 12 weeks), or simvastatin (10–40 mg daily for up to 24 weeks) indicate that the adverse effect profile in children receiving these statins generally is similar to that with placebo. However, elevations in serum CK concentrations exceeding 10 times the upper limit of normal were observed more frequently in children receiving rosuvastatin compared with those receiving placebo. In open-label, uncontrolled studies of 2 years’ duration in pediatric patients 9–16 years of age receiving fluvastatin, the most common adverse effects observed were influenza and infections. There were no detectable adverse effects on growth or sexual maturation in adolescent boys or on duration of menstrual cycle in girls who received atorvastatin, fluvastatin, lovastatin, or simvastatin. In children who received pravastatin, there were no detectable differences in height, weight, testicular volume, Tanner score, or endocrine parameters (i.e., corticotropin [ACTH], cortisol, dehydroepiandrosterone sulfate [DHEA-S], follicle-stimulating hormone [FSH], luteinizing hormone [LH], thyrotropin [TSH], estradiol [in girls], testosterone [in boys]) relative to placebo-treated children. In children 10–17 years of age who received rosuvastatin, there were no detectable adverse effects on growth, weight, body mass index (BMI), or sexual maturation. If therapy with a statin is considered, the manufacturers of atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin state that adolescent girls should be advised to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy. (See Cautions: Pregnancy, Fertility, and Lactation.) Pharmacologic therapy generally should be undertaken in consultation with a specialist in the treatment of pediatric dyslipidemia.

Controversy exists regarding the implementation of screening for elevated cholesterol concentrations and use of long-term cholesterol-lowering interventions in children and adolescents based on the anticipated and/or demonstrated effects of dietary modification on LDL-cholesterol concentrations, the delayed effect of cholesterol-lowering therapy on cardiovascular risk reduction, and the potential for adverse effects related to such cholesterol-lowering interventions. The long-term safety of statins for any age group has not been fully elucidated to date. Safety data from clinical trials in hypercholesterolemic adults receiving statins for 2–8 years suggest that these drugs are well tolerated with an adverse effect profile similar to that of placebo, but long-term data are limited and additional follow-up is needed. The uncertainty about potential long-term toxicity of statins is of particular concern in pediatric patients, since they might be most susceptible to any potential adverse effects resulting from chronic suppression of cholesterol biosynthesis. For additional details regarding the use of specific statins in pediatric patients, see Pediatric Precautions in the individual statin monographs in 24:06.08.

Geriatric Precautions

Statins generally are well tolerated in geriatric patients; the adverse effect profile reported in patients older than 65 years of age is similar to that in younger adults. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience has not revealed age-related differences in response, the possibility that some geriatric patients may exhibit increased sensitivity to statins cannot be ruled out.

Evidence suggests that substantial benefit in cardiovascular risk reduction for geriatric patients may occur with efforts to decrease serum cholesterol concentrations. However, because advanced age (65 years of age or older) is a predisposing factor for myopathy, statins should be used with caution in geriatric patients. (See Musculoskeletal Effects under Cautions: Precautions and Contraindications.) In addition, the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric individuals should be considered when assessing the potential benefit of antilipemic therapy. Because patients older than 75 years of age may have a higher risk of adverse effects and lower adherence to therapy, AHA/ACC guideline states that the expected benefits versus adverse effects of statin therapy should be considered before initiating statin therapy in this population.

Mutagenicity and Carcinogenicity

Statins did not exhibit mutagenic potential in vitro with or without metabolic activation in microbial mutagen tests, forward mutation assays, chromosomal aberration tests, and gene conversion assays.

In rats and mice receiving oral dosages of statins that produced plasma concentrations or AUCs 1–50 times higher than plasma concentrations or AUCs in humans receiving usual dosages of statins for 2 years, there was an increased incidence of hepatocellular adenomas and carcinomas, forestomach squamous papillomas and carcinomas, thyroid follicular adenomas and carcinomas, lung adenomas, and adenomas of the Harderian gland.

While the number of cases of breast cancer in patients receiving pravastatin was higher than that with placebo in one clinical trial, the expected number of breast cancer cases in the placebo group was low compared with that in the general population for women of similar race and age, and data from another study (the Long-term Intervention with Pravastatin in Ischaemic Disease [LIPID] study) indicate a similar incidence of breast cancer among pravastatin- and placebo-treated patients. Long-term (median duration of 7.4 years) follow-up data from the Scandinavian Simvastatin Study (4S) demonstrated a slightly lower incidence of cancer deaths (not statistically significant) in patients treated with simvastatin than in placebo recipients. However, a recent meta-analysis of randomized, controlled statin trials with patient follow-up of at least 1 year in which cancer diagnosis or cancer deaths were reported showed no effect of statins on cancer incidence or cancer death.

While early animal studies raised concerns about the possible carcinogenic effects of simvastatin, a large body of evidence indicates that long-term statin therapy is not associated with an increased risk of cancer. However, the fixed combination of simvastatin and ezetimibe (Vytorin) was reported in one study (the Simvastatin and Ezetimibe in Aortic Stenosis [SEAS] study) to be possibly associated with an increased risk of cancer. Results of this study in 1873 patients with mild to moderate asymptomatic aortic stenosis revealed a higher incidence of cancer and fatal cancer (11.1 and 4.1%, respectively) in patients receiving the fixed-combination preparation compared with those receiving placebo (7.5 and 2.5%, respectively). Findings from the SEAS study prompted FDA to issue an early communication in 2008 about this potential safety risk. However, results of 2 subsequent large randomized studies (the Study of Heart and Renal Protection [SHARP] and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]) found no consistent pattern of increased cancer risk among patients receiving the fixed-combination preparation. Based on the currently available evidence, FDA has concluded that the fixed-combination preparation of ezetimibe and simvastatin (Vytorin) is not likely to increase the risk of cancer.

Pregnancy, Fertility, and Lactation

Pregnancy

Treatment of hyperlipidemia is generally not necessary during pregnancy and it is recommended that statin therapy be discontinued in most patients who are pregnant. Since atherosclerosis is a chronic process, discontinuance of antilipemic agents during pregnancy generally should not have a substantial effect on the long-term outcome of primary hyperlipidemia in most patients. Experts recommend that dyslipidemias in pregnant women be managed with dietary measures; consultation with a lipid specialist is recommended for pregnant women with severe forms of dyslipidemia (e.g., homozygous familial hypercholesterolemia).

All statins were previously contraindicated in pregnant women because the fetal risk with these drugs was thought to outweigh any possible benefit. This determination was based on several factors including safety signals from animal data. In addition, congenital anomalies including severe CNS defects and unilateral limb deficiencies were reported in a case series of pregnant women who were exposed to a lipophilic statin during the first trimester. Because statins decrease synthesis of cholesterol and possibly other products of the cholesterol biosynthetic pathway, there is also a concern that these drugs can potentially cause fetal harm. More recent data from case series and observational cohort studies have not shown evidence of an increased risk of major birth defects with statin use during pregnancy, and this was observed after controlling for potential confounders such as maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use. The overall evidence from animal studies suggests limited potential for statins to cause malformations or other adverse fetal effects. While an increased risk of miscarriage has been reported in pregnant women exposed to statins, it is not clear whether this effect is related to the drugs or to other confounding factors. FDA conducted a comprehensive review of all available clinical and nonclinical data related to statin use in pregnant women and concluded that the totality of evidence suggests that there is limited potential for statins to cause malformations and other adverse embryofetal effects. Because statins may prevent serious or potentially fatal cardiovascular events in certain high-risk patients who are pregnant, FDA has requested that the contraindication in pregnant women be removed from the prescribing information for all statins. While FDA still advises that most pregnant patients discontinue statins because of the possibility of fetal harm, there may be some patients (e.g., those with homozygous familial hypercholesterolemia or established cardiovascular disease) in whom continued therapy may be beneficial; therefore, decisions should be individualized based on the patient's risks versus benefits. Patients who become pregnant or suspect that they are pregnant while receiving a statin should notify their clinician who can advise them on the appropriate course of action.

Fertility

Effects of statins on spermatogenesis and fertility have not been studied in adequate numbers of patients. In animals receiving statins, no adverse effects on fertility were observed. However, in male rats receiving certain statins (e.g., simvastatin) in dosages resulting in AUCs of 4 times the maximum human exposure level for 34 weeks, decreased fertility was observed. This effect was not reproduced during a subsequent study using the same drug and dosage for 11 weeks (the entire duration of the spermatogenesis cycle in rats, including epididymal maturation). Seminiferous tubule degeneration, testicular atrophy, decreased spermatogenesis, spermatocytic degeneration, and giant cell formation were observed. The clinical importance of these effects has not been established.

Lactation

Some statins (e.g., fluvastatin, pravastatin) are distributed into human milk. Because of the potential for serious adverse reactions from these drugs in nursing infants, statins are contraindicated in nursing women; women who are taking these drugs should be advised not to breast-feed their infants. Many patients can stop statin therapy temporarily until breast-feeding is complete; patients who require ongoing statin treatment should not breast-feed and should use alternatives such as infant formula.

Drug Interactions

Drugs and Foods Affecting or Metabolized by Hepatic Microsomal Enzymes

Current evidence suggests that certain adverse effects of statins (i.e., myotoxicity) are more common in patients receiving concomitant therapy with drugs metabolized by the hepatic cytochrome P-450 (CYP) isoenzyme system. Metabolism of most statins is mediated by the CYP isoenzyme system (see Elimination under Pharmacokinetics), principally by CYP3A4 and 2C9; concomitant use of drugs that inhibit these isoenzymes may increase plasma concentrations of these statins and increase the risk of adverse effects. Conversely, drugs that induce CYP isoenzymes may reduce plasma concentrations of statins metabolized by these isoenzymes. The clinical importance of these CYP-mediated interactions is based on the degree of inhibition or induction of CYP enzymes and the pharmacokinetic profile of the individual statin.

Atorvastatin, lovastatin, and simvastatin are metabolized by the cytochrome P-450 isoenzyme 3A4 (CYP3A4) and are contraindicated, should be avoided, or used with extreme caution in patients receiving certain drugs or foods that inhibit CYP3A4 (e.g., cyclosporine, erythromycin, clarithromycin, efavirenz, itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors [PIs], nefazodone, cobicistat-containing preparations, grapefruit juice). Simvastatin and lovastatin are substantially metabolized by CYP3A4 and, therefore, subject to more drug interactions that may require intervention. Fluvastatin, pitavastatin, pravastatin, and rosuvastatin are not substantially metabolized by CYP3A4; however, some clinicians and the manufacturer recommend that rosuvastatin be used with caution in patients receiving certain HIV or hepatitis C virus (HCV) PIs (e.g., certain ritonavir-boosted HIV PIs, simeprevir [no longer commercially available in the US]). Atorvastatin also undergoes CYP3A4 metabolism, but to a lesser extent. Fluvastatin, pitavastatin, and rosuvastatin are principally metabolized by CYP2C9, and pravastatin does not undergo CYP metabolism.

Antifungals

Rhabdomyolysis has occurred in at least one patient receiving concomitant lovastatin and itraconazole therapy. Concomitant use of itraconazole with lovastatin or simvastatin has resulted in a 10- to 20-fold increase in plasma concentrations of the antilipemic agents and more than a 14.8- to 36-fold increase in the area under the plasma concentration-time curve (AUC) of lovastatin. Itraconazole increased peak plasma concentration and AUC of atorvastatin by approximately 20% and 3.3-fold, respectively; of pravastatin by approximately 17 and 11%, respectively; and of rosuvastatin by 1.2- to 1.4-fold and 1.3- to 1.4-fold, respectively. Itraconazole decreased peak plasma concentration and AUC of pitavastatin by 22 and 23%, respectively. Concomitant administration of itraconazole with fluvastatin did not result in clinically important alterations in the pharmacokinetic profile of either drug.

Other azole antifungals that inhibit CYP3A4 (e.g., fluconazole, ketoconazole, posaconazole, voriconazole) also may inhibit the metabolism of certain statins, resulting in increased statin concentrations and an increased risk of myopathy and/or rhabdomyolysis. There is some evidence that voriconazole is a less potent inhibitor of CYP3A4 than ketoconazole or itraconazole; however, voriconazole has been shown to inhibit lovastatin metabolism in vitro and is likely to increase plasma concentrations of lovastatin and other statins metabolized by CYP3A4.

The manufacturer of atorvastatin states that clinicians considering concomitant use of atorvastatin with azole antifungals should weigh the benefits and risks (e.g., myopathy, rhabdomyolysis) of such concomitant use and should carefully monitor patients for manifestations of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and following an increase in dosage of either drug; in addition, if atorvastatin is used concomitantly with itraconazole, the lowest necessary dosage of atorvastatin should be employed, and dosage of atorvastatin should be limited.

If fluvastatin and fluconazole are used concomitantly, dosage of fluvastatin should be limited.

Because of an increased risk of myopathy and/or rhabdomyolysis, concomitant administration of lovastatin or simvastatin with itraconazole, ketoconazole, posaconazole, or voriconazole is contraindicated; if therapy with itraconazole, ketoconazole, posaconazole, or voriconazole is unavoidable, therapy with lovastatin or simvastatin must be suspended during the course of antifungal treatment.

The manufacturer of voriconazole states that if voriconazole must be used concomitantly with a statin, the patient should be monitored frequently for statin-associated adverse effects and toxicity, and dosage adjustment of the statin should be considered and may be needed to reduce the risk of myopathy, including rhabdomyolysis.

Antimycobacterials

Concomitant use of atorvastatin with rifampin may result in variable reductions in plasma concentrations of atorvastatin; administration of rifampin followed by delayed administration of atorvastatin resulted in 40 and 80% decreases in atorvastatin peak plasma concentration and AUC, respectively, while simultaneous administration of the drugs resulted in 2.7-fold and 30% increases in atorvastatin peak plasma concentration and AUC, respectively. Concomitant use of pitavastatin and rifampin increased pitavastatin peak plasma concentration and AUC by twofold and 29%, respectively, and decreased rifampin peak plasma concentration and AUC by 18 and 15%, respectively. Following concomitant administration with rifampin, peak plasma concentration and AUC of fluvastatin decreased by 42 and 53%, respectively.

The manufacturer of atorvastatin states that if atorvastatin and rifampin are used concomitantly, these drugs should be administered simultaneously, as delayed administration of atorvastatin following administration of rifampin has been associated with substantial reductions in plasma concentrations of atorvastatin.

The manufacturer of pitavastatin states that if this statin and rifampin are used concomitantly, dosage of pitavastatin should be limited.

Antiretroviral Agents

HIV Protease Inhibitors

Concomitant use of certain statins (e.g., atorvastatin, lovastatin, rosuvastatin, simvastatin) with HIV protease inhibitors (atazanavir, darunavir, indinavir, fosamprenavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) increases plasma concentration and AUC of the antilipemic agent, resulting in increased effects and/or increased risk of toxicity (e.g., myopathy and/or rhabdomyolysis).

Concomitant use of HIV protease inhibitors with lovastatin or simvastatin is contraindicated.

The manufacturer of atorvastatin states that concomitant use of atorvastatin and ritonavir-boosted tipranavir should be avoided. In addition, the manufacturer states that the benefits of concomitant use of atorvastatin with fosamprenavir (with or without low-dose ritonavir), the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir), ritonavir-boosted darunavir, or ritonavir-boosted saquinavir should be weighed against the possible risk of myopathy or rhabdomyolysis, and patients should be monitored carefully for manifestations of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and following an increase in dosage of either drug. If atorvastatin is used concomitantly with fosamprenavir (with or without low-dose ritonavir), nelfinavir, ritonavir-boosted darunavir, or ritonavir-boosted saquinavir, caution is advised; the lowest necessary dosage of atorvastatin should be used, and dosage of atorvastatin should be limited. If atorvastatin is used concomitantly with lopinavir/ritonavir, caution is advised, and the lowest necessary dosage of atorvastatin should be used.

If rosuvastatin is used concomitantly with ritonavir-boosted or cobicistat-boosted HIV protease inhibitors, caution is advised because such concomitant use has differing effects on exposure to rosuvastatin; dosage of rosuvastatin should be limited during concomitant therapy with ritonavir-boosted atazanavir or lopinavir/ritonavir.

If pravastatin is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, some experts state that pravastatin dosage should be titrated carefully while monitoring for pravastatin-associated adverse effects since concomitant use with ritonavir-boosted darunavir increased pravastatin AUC by 81%. Some experts and FDA state that dosage adjustments are not necessary when pitavastatin is used concomitantly with HIV protease inhibitors, or when pravastatin is used concomitantly with lopinavir/ritonavir or ritonavir-boosted saquinavir.

Nonnucleoside Reverse Transcriptase Inhibitors

Concomitant use of certain statins (e.g., atorvastatin, lovastatin, simvastatin) and certain nonnucleoside reverse transcriptase inhibitors (efavirenz, etravirine, nevirapine) may alter plasma concentrations of the antilipemic agent.

Concomitant use of efavirenz with atorvastatin, pravastatin, or simvastatin has resulted in decreased AUC of the antilipemic agent. If efavirenz is used in patients receiving atorvastatin, pravastatin, or simvastatin, dosage of the antilipemic agent should be adjusted according to lipid response (up to the maximum recommended dosage).

Etravirine has been shown to decrease atorvastatin AUC; the drug may increase fluvastatin concentrations and decrease pravastatin, lovastatin, or simvastatin concentrations, but is not expected to have substantial effects on pitavastatin or rosuvastatin concentrations. If etravirine is used in patients receiving atorvastatin, lovastatin, pravastatin, or simvastatin, dosage of the antilipemic agent should be adjusted according to lipid response (up to the maximum recommended dosage); if etravirine is used with fluvastatin, dosage adjustments for fluvastatin may be necessary. If etravirine is used in patients receiving rosuvastatin, dosage adjustments are not needed.

Nevirapine may decrease lovastatin or simvastatin concentrations. If nevirapine is used in patients receiving lovastatin or simvastatin, dosage of the antilipemic agent should be adjusted according to lipid response (up to the maximum recommended dosage).

Rilpivirine has been shown to increase concentrations of atorvastatin metabolites but does not affect atorvastatin AUC; dosage adjustments are not needed.

Cardiac Drugs

Amiodarone

Amiodarone is metabolized by the CYP microsomal enzyme system, principally by the isoenzyme CYP3A4. In addition, amiodarone inhibits the activity of CYP3A4 and potentially may interact with drugs that also are metabolized by this enzyme. Concomitant use of simvastatin and amiodarone increased simvastatin peak plasma concentration and AUC by 1.79- and 1.76-fold, respectively.

Because the risk of myopathy or rhabdomyolysis is increased following concomitant use of amiodarone with certain statins (e.g., lovastatin, simvastatin), dosages of these statins should be limited during concomitant therapy. In addition, the benefits versus risks of such concomitant therapy should be considered.

Diltiazem

Concomitant use of atorvastatin with diltiazem did not alter atorvastatin peak plasma concentration, but atorvastatin AUC was increased by 51%; in addition, rhabdomyolysis with renal failure and acute hepatitis have been reported in at least one patient receiving these agents concomitantly.

Concomitant administration of various other statins (e.g., lovastatin, simvastatin) and diltiazem has resulted in marked increases (i.e., 257–333% and fourfold to fivefold, respectively) in plasma concentrations of the antilipemic agents. Because the risk of myopathy and/or rhabdomyolysis is increased in patients receiving lovastatin or simvastatin (particularly with higher dosages of the statin) concomitantly with diltiazem, dosage of lovastatin or simvastatin should be limited during concomitant therapy. In addition, the benefits versus risks of such concomitant therapy should be considered.

Concomitant use of pitavastatin and extended-release diltiazem increased pitavastatin peak plasma concentration and AUC by 15 and 10%, respectively, and decreased diltiazem peak plasma concentration and AUC by 7 and 2%, respectively.

Concomitant use of pravastatin and diltiazem increased pravastatin peak plasma concentration and AUC by 30 and 2.7%, respectively.

Dronedarone

The risk of myopathy, including rhabdomyolysis, is increased following concomitant use of dronedarone with certain statins (e.g., lovastatin, simvastatin).

Concomitant administration of dronedarone and simvastatin increased peak plasma concentration and AUC of simvastatin by 3.75- and 3.9-fold, respectively; peak plasma concentration and AUC of the active simvastatin acid metabolite were increased by 2.14- and 1.96-fold, respectively. While there are no specific studies evaluating the interaction potential between dronedarone and lovastatin, it is expected that dronedarone also may increase lovastatin exposure to the same degree as simvastatin. The manufacturers of lovastatin and simvastatin state that dosage of these statins should be limited if used concomitantly with dronedarone and the benefits versus risks of such concomitant therapy should be carefully considered.

Verapamil

Concomitant use of certain statins (e.g., lovastatin, simvastatin) with verapamil increases the risk of myopathy and/or rhabdomyolysis. In a randomized, double-blind, crossover study in healthy individuals, concomitant administration of verapamil with simvastatin resulted in a threefold to fivefold increase in simvastatin concentrations and a threefold increase in simvastatin acid concentrations. In addition, concomitant use of simvastatin and extended-release verapamil increased simvastatin and simvastatin acid peak plasma concentration (2.1- and 2.4-fold, respectively) and AUC (2.5- and 2.3-fold, respectively). Because of such risk, some clinicians state that concomitant use of simvastatin and verapamil generally should be avoided. However, if concomitant use with verapamil is necessary, dosages of lovastatin and simvastatin should be limited, and close monitoring for adverse effects (i.e., muscle tenderness, elevated CK concentrations) is advised. In addition, the benefits versus risks of such concomitant therapy should be considered.

It has been suggested that since fluvastatin and pravastatin are not substantially metabolized by the CYP3A4 isoenzyme, verapamil would not be expected to have a clinically important effect on the pharmacokinetics of these statins. However, concomitant use of pravastatin and verapamil (immediate- and extended-release) has been shown to increase pravastatin peak plasma concentration and AUC by 42 and 31%, respectively.

Cobicistat-containing Preparations

Concomitant use of cobicistat-containing preparations and certain statins (e.g., lovastatin, simvastatin) can increase plasma concentrations of the antilipemic agent, and possibly increase the risk of myopathy and/or rhabdomyolysis. The manufacturers of lovastatin and simvastatin state that concomitant use of cobicistat-containing preparations with these statins is contraindicated.

Danazol

Myositis with rhabdomyolysis has developed in at least one patient receiving lovastatin and danazol concomitantly. Although the mechanism of the interaction has not been fully elucidated, it has been suggested that this adverse effect probably resulted from danazol-induced inhibition of lovastatin metabolism (by CYP3A4). Because the risk of myopathy and/or rhabdomyolysis is increased in patients receiving danazol concomitantly with certain statins, the manufacturer states that dosage of lovastatin should be limited during concomitant therapy with danazol; in addition, the benefits versus risks of such concomitant therapy should be considered.

Concomitant use of simvastatin with danazol is contraindicated. The risk of myositis with rhabdomyolysis in patients receiving danazol with other statins currently is not known.

Grapefruit Juice

Grapefruit juice is a potent inhibitor of the CYP3A4 isoenzyme and can increase plasma concentrations of various statins metabolized by CYP3A4 (e.g., atorvastatin, lovastatin, simvastatin).

The extent of this interaction may be influenced by the quantity and timing of grapefruit juice consumption (relative to administration of the statin) and also may vary depending on the specific statin used. In several studies in healthy individuals, plasma concentrations of lovastatin or simvastatin were increased by approximately twofold following administration of regular-strength grapefruit juice (240 mL) with breakfast and a single dose of lovastatin (40 mg) or simvastatin (20 mg) in the evening. In several other studies in individuals who received repeated quantities of double-strength grapefruit juice concomitantly with a single dose of atorvastatin (40 mg), lovastatin (80 mg), or simvastatin (60 mg), plasma concentrations of the antilipemic agents were increased by approximately 3.3-, 15-, or 16-fold, respectively. In a crossover study in healthy individuals, concurrent administration of simvastatin (40 mg) with large amounts of grapefruit juice (200 mL double-strength 3 times daily for 3 days) increased peak plasma concentrations and AUC of simvastatin by 12- and 13.5-fold, respectively; however, the inhibitory effects of grapefruit juice were considerably decreased when simvastatin was taken 24 hours after ingestion of grapefruit juice. In a study evaluating the interaction potential of grapefruit juice and atorvastatin, concomitant administration of a single dose of atorvastatin (40 mg) with grapefruit juice (240 mL once daily) increased atorvastatin peak plasma concentration and AUC by 16 and 37%, respectively; more substantial increases in atorvastatin peak plasma concentration (up to 71%) and/or AUC (up to 2.5-fold) have been reported following ingestion of large quantities (750–1200 mL daily or more) of grapefruit juice.

Because the risk of myopathy may be increased with high plasma concentrations of statins, the manufacturers of lovastatin and simvastatin and some clinicians state that concomitant administration of these statins with grapefruit juice should be avoided. The manufacturer of atorvastatin states that the risk of myopathy may be increased with ingestion of large quantities (more than one liter daily) of grapefruit juice. However, there is some difference of opinion regarding the actual risk of this drug interaction versus the perceived risk based on studies that used unusually large volumes of grapefruit juice. Some clinicians suggest that a small amount of grapefruit juice (e.g., 240 mL regular-strength) may be acceptable and may even be used to therapeutic advantage, although consumption should be separated from statin administration (i.e., grapefruit juice given in the morning and statin in the evening) to minimize this potentially serious interaction. Because of interindividual variations in CYP3A4-mediated drug metabolism and other factors, some patients may be more susceptible to the interacting effects of grapefruit juice.

Concomitant administration of grapefruit juice does not appear to affect the pharmacokinetics of fluvastatin, pitavastatin, or pravastatin because CYP3A4 is either not involved or only minimally involved in the metabolism of these statins.

Immunosuppressive Agents

Cyclosporine has been shown to increase AUC of statins. Concomitant administration of atorvastatin or lovastatin with cyclosporine resulted in an 8.7-fold increase in atorvastatin AUC and a fivefold to eightfold increase in lovastatin AUC. Cyclosporine increased pitavastatin peak plasma concentration and AUC by 6.6- and 4.6-fold, respectively; such effects are considered clinically important. In addition, myopathy and/or rhabdomyolysis has developed in some patients receiving cyclosporine concomitantly with certain statins (e.g., atorvastatin, lovastatin, simvastatin). Although the mechanism of the interaction has not been fully elucidated, it has been suggested that this adverse effect probably results from cyclosporine-induced inhibition of statin metabolism (by CYP3A4); cyclosporine-induced inhibition of organic anion transporter (OATP) 1B1 also may be responsible for increasing bioavailability of atorvastatin, pitavastatin, and simvastatin acid. Concomitant administration of cyclosporine with fluvastatin, pravastatin, or rosuvastatin has resulted in substantial increases in the peak plasma concentration (i.e., 30%, 327%, or 11-fold, respectively) or AUC (i.e., 90%, 282%, or sevenfold, respectively) of the antilipemic agent. However, neither myopathy nor substantial increases in CK concentrations have been observed in 3 reports involving 100 posttransplant patients (24 renal and 76 cardiac) receiving concomitant therapy with cyclosporine and pravastatin for up to 2 years.

The manufacturers of pitavastatin and simvastatin state that concomitant use of these statins with cyclosporine is contraindicated. The manufacturers of atorvastatin and lovastatin state that concomitant use of these statins with cyclosporine should be avoided. The manufacturers of fluvastatin, pravastatin, and rosuvastatin state that dosages of these statins should be limited during concomitant therapy with cyclosporine.

Although data are more limited with everolimus, sirolimus, and tacrolimus, the drug interaction potential of these other immunosuppressants is expected to be similar to that of cyclosporine because of similar metabolism. Some experts state that concomitant use of everolimus, tacrolimus, or sirolimus with lovastatin, pitavastatin, or simvastatin should be avoided. These experts state that if atorvastatin is used concomitantly with any of these immunosuppressants, dosage of the statin should be limited.

Macrolides

Rhabdomyolysis with or without renal impairment has occurred in patients receiving erythromycin or clarithromycin concomitantly with certain statins (e.g., lovastatin). Certain macrolides, including erythromycin, clarithromycin, and telithromycin (no longer commercially available in the US) are inhibitors of the CYP3A4 isoenzyme. Concomitant administration of erythromycin with atorvastatin or simvastatin resulted in marked increases (i.e., 38%, or fourfold to sixfold, respectively) in plasma concentrations of the antilipemic agents. Concomitant administration of clarithromycin with atorvastatin or pravastatin resulted in increased peak plasma concentrations (i.e., 5.4-fold and 128%, respectively) and AUC (i.e., 4.4-fold and 110%, respectively) of the antilipemic agents. Erythromycin increased pitavastatin peak plasma concentration and AUC by 3.6- and 2.8-fold, respectively; such effects are considered clinically important. Concomitant use of erythromycin with rosuvastatin decreased rosuvastatin peak plasma concentration and AUC by 31 and 20%, respectively. No clinically important changes in the pharmacokinetic profile of fluvastatin or pravastatin were reported following concomitant administration with erythromycin.

The manufacturer of atorvastatin states that the benefits of concomitant use of atorvastatin with macrolide antibiotics (e.g., clarithromycin, erythromycin) should be weighed against the possible risk of myopathy or rhabdomyolysis, and patients should be monitored carefully for manifestations of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and following an increase in dosage of either drug. If atorvastatin is used concomitantly with clarithromycin, caution is advised; the lowest necessary dosage of atorvastatin should be used, and dosage of atorvastatin should be limited. If atorvastatin is used concomitantly with other macrolide antibiotics (e.g., erythromycin), caution is advised and lower initial and maintenance dosages of atorvastatin should be considered.

Because of an increased risk of myopathy and/or rhabdomyolysis, concomitant use of lovastatin or simvastatin with clarithromycin or erythromycin is contraindicated. If therapy with these macrolide antibiotics is unavoidable, therapy with lovastatin or simvastatin must be suspended during the course of macrolide treatment.

If pitavastatin and erythromycin are used concomitantly, dosage of pitavastatin should be limited.

If pravastatin and clarithromycin are used concomitantly, dosage of pravastatin should be limited. Other macrolides (e.g., erythromycin, azithromycin) also may potentially increase exposure to pravastatin and should therefore be used concomitantly with caution.

Nefazodone

Administration of single 40-mg doses of atorvastatin or simvastatin in healthy individuals who had received nefazodone (200 mg twice daily) for 6 days resulted in threefold to fourfold increases in plasma concentrations of atorvastatin and atorvastatin lactone and 20-fold increases in plasma concentrations of simvastatin and simvastatin acid. In addition, myositis or rhabdomyolysis has occurred in a few patients following concomitant therapy with nefazodone and various statins (e.g., lovastatin, simvastatin). Although the mechanism of the interaction has not been fully elucidated, it has been suggested that this adverse effect probably resulted from nefazodone-induced inhibition of statin metabolism and subsequent marked increases in plasma concentrations of the antilipemic agent. Concomitant administration of pravastatin with nefazodone has resulted in increased serum CK concentrations in at least one patient.

Because of the risk of rhabdomyolysis, the manufacturer of nefazodone suggests that concomitant administration of nefazodone and certain statins (e.g., atorvastatin, lovastatin, simvastatin) be used with caution and at reduced dosages. However, the manufacturers of lovastatin and simvastatin and some clinicians state that concomitant use of nefazodone with lovastatin or simvastatin is contraindicated.

Oral Antidiabetic Agents

Concomitant oral administration of glyburide or tolbutamide with certain statins (e.g., fluvastatin, simvastatin) reportedly has resulted in increased bioavailability of the antidiabetic agents without altering oral glucose tolerance. It has been suggested that these interactions probably resulted from inhibition of the CYP microsomal enzyme system (e.g., CYP2C9) involved in the metabolism of both agents. Although concomitant administration of fluvastatin with glyburide did not substantially alter the hypoglycemic effects of the antidiabetic agent, the manufacturer of fluvastatin recommends that patients receiving concomitant therapy with fluvastatin and glyburide should continue to be monitored appropriately.

Acid-reducing Agents

Concomitant administration of fluvastatin with cimetidine, ranitidine, or omeprazole resulted in increased peak plasma concentrations (40, 50, or 37%, respectively) and AUC (30, 10, or 20%, respectively) of fluvastatin. Although the mechanism of the interaction has not been fully elucidated, this effect probably resulted from a reduction in acid-catalyzed degradation of the antilipemic agent. It has been suggested that cimetidine also may inhibit the CYP enzyme system, resulting in increased concentrations of fluvastatin. Concomitant administration of cimetidine with atorvastatin or pravastatin decreased atorvastatin peak plasma concentration and AUC by 11 and less than 1%, respectively, and increased pravastatin peak plasma concentration and AUC by 9.8 and 30%, respectively.

Amlodipine

The risk of myopathy, including rhabdomyolysis, is increased following concomitant use of simvastatin with amlodipine. Concomitant use of simvastatin and amlodipine increased simvastatin peak plasma concentration and AUC by 1.47- and 1.77-fold, respectively. The manufacturer of simvastatin states that if this statin and amlodipine are used concomitantly, dosage of simvastatin should be limited, and the benefits versus risks of such concomitant therapy should be considered.

Concomitant use of atorvastatin and amlodipine decreased atorvastatin peak plasma concentration by 12%, while increasing atorvastatin AUC by 15%.

Antacids

Concomitant administration of atorvastatin with an antacid containing aluminum hydroxide and magnesium hydroxide resulted in 34 and 33% decreases in atorvastatin peak plasma concentration and AUC, respectively.

Simultaneous administration of rosuvastatin and an antacid containing aluminum hydroxide and magnesium hydroxide decreased rosuvastatin peak plasma concentration and AUC by 50 and 54%, respectively; such effects were considered clinically important. In contrast, when rosuvastatin and the antacid were administered 2 hours apart, rosuvastatin peak plasma concentration and AUC were decreased by 16 and 22%, respectively. Antacids containing aluminum and magnesium hydroxides should be administered at least 2 hours after rosuvastatin.

Antilipemic Agents

Bile Acid Sequestrants

The cholesterol-lowering effects of statins and bile acid sequestrants (e.g., cholestyramine, colestipol) are additive or synergistic.

Concomitant use of atorvastatin and colestipol decreased atorvastatin peak plasma concentration by 26%. When fluvastatin was administered 4 hours after cholestyramine and a meal, peak plasma concentration and AUC of fluvastatin were decreased by 83 and 51%, respectively. When pravastatin (20 mg as a single dose) was administered with cholestyramine (4 g as a single dose) or colestipol (10 g as a single dose), peak plasma concentration and AUC of pravastatin decreased by 39–53 and 40–47%, respectively. However, when pravastatin was administered 1 hour prior to cholestyramine, peak plasma concentration and AUC of pravastatin increased by 30 and 12%, respectively; when pravastatin was administered 4 hours after cholestyramine, peak plasma concentration and AUC of pravastatin decreased by 6.8 and 12%, respectively. Concomitant use of pravastatin (5–20 mg twice daily for 8 weeks) and cholestyramine (24 g once daily for 4 weeks) decreased pravastatin AUC by 18–51% but produced variable effects on pravastatin peak plasma concentration.

Therefore, some statin manufacturers recommend that statins be administered either 1 hour or more before, or at least 4 hours after, a bile acid sequestrant when these agents are used concomitantly.

Fibric Acid Derivatives

Since both drugs are independently associated with a risk of muscle toxicity, the risk of myopathy and rhabdomyolysis is increased in patients receiving statins concomitantly with fibric acid derivatives (e.g., gemfibrozil). Severe (with or without renal failure) and, rarely, fatal rhabdomyolysis has occurred in some patients receiving cerivastatin (no longer commercially available in the US) concomitantly with gemfibrozil. (See Cautions: Musculoskeletal Effects.) Muscle-related toxicity also has been reported with other statin-fibric acid derivative combinations. In controlled clinical trials in nearly 600 patients receiving such combinations, moderate increases (exceeding 3 times the upper limit of normal) in serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations or discontinuance of therapy because of muscle pain/discomfort was reported in 1% of patients; the reporting rates of mild adverse musculoskeletal effects (e.g., muscle pain) is expected to be similar among statin-fibric acid derivative combinations containing atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin. The precise mechanism of the interaction between statins and fibric acid derivatives has not been fully elucidated; however, it has been suggested that the increased risk of myopathy and/or rhabdomyolysis may have both pharmacokinetic (i.e., decreased statin metabolism) and pharmacodynamic origins.

The manufacturer of simvastatin states that concomitant use of this statin with gemfibrozil is contraindicated, and the manufacturers of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, and rosuvastatin state that concomitant use of these statins with gemfibrozil should be avoided. The 2018 AHA/ACC cholesterol management guideline states that if a fibric acid derivative is necessary in a patient treated with a statin, it is safer to use fenofibrate than gemfibrozil because of a lower risk of myopathy. In a scientific statement, AHA states that some statin-gemfibrozil combinations (i.e., gemfibrozil with atorvastatin, pitavastatin, or rosuvastatin) may be considered if clinically indicated. If gemfibrozil must be used in combination with atorvastatin, pitavastatin, or rosuvastatin, dosage of the statin should be limited.

The manufacturers state that caution is advised if statins are used concomitantly with other fibric acid derivatives (e.g., fenofibrate). In addition, the manufacturers of atorvastatin, lovastatin, pravastatin, and simvastatin state that the benefits (e.g., further alterations in lipid levels) of concomitant use of these statins and fibric acid derivatives other than gemfibrozil (e.g., fenofibrate) should be carefully weighed against the possible risk of myopathy. The manufacturer of atorvastatin also states that lower initial and maintenance dosages of this statin should be considered during such concomitant therapy, and patients should be carefully monitored for manifestations of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and following an increase in dosage of either drug.

Lomitapide

Concomitant use of certain statins (i.e., atorvastatin, lovastatin, rosuvastatin, simvastatin) with lomitapide has resulted in increased exposure to the statin. The manufacturer of lomitapide states that dosage of lomitapide should be limited to 30 mg daily when the drug is used concomitantly with atorvastatin. When lomitapide is used concomitantly with lovastatin, reduction in lovastatin dosage should be considered. When lomitapide is initiated in patients receiving simvastatin, dosage of simvastatin should be reduced by 50%; during concomitant use, dosage of simvastatin should not exceed 20 mg daily (or 40 mg daily in patients who have received the 80-mg daily dosage for at least 1 year without evidence of adverse muscular effects).

Niacin

Concomitant use of statins and niacin (particularly at antilipemic dosages [exceeding 1 g daily]) increases the risk of myopathy and/or rhabdomyolysis. Severe myopathy or rhabdomyolysis has occurred in some patients receiving certain statins concomitantly with antilipemic dosages (exceeding 1 g daily) of niacin. Caution is advised if statins are used concomitantly with antilipemic dosages of niacin; dosage reduction of the statin may be required and patients should be carefully monitored for manifestations of muscle pain, tenderness, or weakness.

The manufacturer of simvastatin recommends against concomitant use of simvastatin and niacin dosages of 1 g or more daily in Chinese patients since risk of myopathy is increased in these patients; it is not known whether this risk applies to other Asian populations.

Omega-3-acid Ethyl Esters

Concomitant use of certain statins (i.e., atorvastatin, rosuvastatin, simvastatin) with omega-3-acid ethyl esters for 14 days did not affect the rate or extent of exposure to these statins or their metabolites at steady state.

Colchicine

Specific drug interaction studies have not been conducted with statins and colchicine to determine whether specific pharmacokinetic parameters are affected when the drugs are used concomitantly; however, myopathy, including rhabdomyolysis, has been reported in patients receiving various statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin) concomitantly with colchicine. The manufacturers generally caution against the concomitant use of these statins with colchicine; however, other experts state that concomitant use of rosuvastatin, fluvastatin, lovastatin, pitavastatin, or pravastatin with colchicine is reasonable when clinically indicated, and concomitant use of atorvastatin or simvastatin with colchicine may be considered in appropriate patients. Dosage reduction for some of these statins should be considered to minimize the risk of potential interaction.

Conivaptan

Cases of muscle-related toxicity have been reported in patients receiving concomitant therapy with conivaptan and simvastatin or lovastatin. Such combinations should be avoided. If concomitant use of a statin and conivaptan is required, some experts state that atorvastatin, pravastatin, fluvastatin, rosuvastatin, or pitavastatin may be considered.

Digoxin

Concomitant administration of digoxin with various statins (e.g., atorvastatin, pitavastatin, pravastatin, rosuvastatin) has resulted in variable effects on plasma digoxin concentrations. Concomitant use of atorvastatin 80 mg and digoxin increased peak plasma concentration and AUC of digoxin by 20 and 15%, respectively; however, atorvastatin 10 mg did not alter the pharmacokinetics of digoxin. Concomitant use of lovastatin and digoxin in patients with hypercholesterolemia had no effect on plasma concentrations of digoxin. Concomitant use of fluvastatin and digoxin increased fluvastatin peak plasma concentration by 11% while not affecting fluvastatin AUC. Concomitant use of pitavastatin and digoxin decreased pitavastatin peak plasma concentration by 9% while increasing pitavastatin AUC by 4%. Concomitant use of pravastatin and digoxin increased pravastatin peak plasma concentration and AUC by 26 and 23%, respectively. Patients receiving digoxin should be monitored appropriately, particularly when statins are initiated.

Estrogens/Progestins

Concomitant administration of atorvastatin or rosuvastatin with an oral contraceptive increased peak plasma concentrations and AUC of the oral contraceptive components (i.e., ethinyl estradiol, norethindrone, norgestrel). The manufacturer of atorvastatin states that this interaction should be considered when selecting oral contraceptives for patients receiving atorvastatin or other statins.

Ranolazine

The risk of myopathy, including rhabdomyolysis, is increased following concomitant use of lovastatin or simvastatin with ranolazine. Concomitant use of simvastatin and ranolazine increased simvastatin or simvastatin acid peak plasma concentration by 1.75- or 2.28-fold, respectively, and AUC by 1.86- or 2.26-fold, respectively. The manufacturer of lovastatin states that dosage adjustment of lovastatin may be considered during concomitant therapy with ranolazine. The manufacturer of simvastatin states that dosage of simvastatin should be limited when used concomitantly with ranolazine, and the risks versus benefits of such concomitant therapy should be carefully considered.

Sacubitril/Valsartan

Interactions mediated by the organic anion-transporting polyprotein (OATP) and the organic anion transporter (OAT) are possible when certain statins (e.g., atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) are administered concomitantly with sacubitril/valsartan. Some experts recommend that lower doses of these statins be considered during concomitant use.

Ticagrelor

Concomitant use of atorvastatin and ticagrelor increased atorvastatin peak plasma concentration and AUC by 23 and 36%, respectively; however, these changes were not statistically significant. Ticagrelor increased peak plasma concentration and AUC of simvastatin by 81 and 56%, respectively, with some individuals experiencing even greater increases in simvastatin exposure. Some experts state that dosage of simvastatin or lovastatin should not exceed 40 mg daily when administered concomitantly with ticagrelor.

Warfarin

Increased prothrombin time/international normalized ratio (PT/INR) and/or clinically evident bleeding have been reported in patients receiving warfarin concomitantly with various statins (e.g., fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin). Such effects have not been observed in patients receiving atorvastatin or pitavastatin concomitantly with warfarin. While the mechanism of this interaction has not been established, it has been proposed that highly protein-bound statins (e.g., lovastatin) may displace warfarin from plasma protein-binding sites. Some clinicians also suggest that certain statins (e.g., lovastatin) may inhibit warfarin metabolism. Since fluvastatin is principally metabolized by CYP2C9, it may be expected to inhibit the metabolism of S-warfarin and thereby increase the anticoagulant response. Concomitant use of some statins and warfarin also may result in altered peak plasma concentrations and AUC of the drugs. PT/INR should be monitored closely until stabilized when a statin is initiated or dosage adjusted in patients receiving warfarin.

Acute Toxicity

Limited information is available on the acute toxicity of statins.

Manifestations

A few cases of accidental statin overdosage have been reported. Although accidental ingestion of single oral doses of lovastatin as high as 3–75 times the maximum recommended human oral daily dosage resulted in no toxic effect, various adverse GI effects and increases in serum transaminase concentrations were reported with a 2-week ingestion of 640 mg of fluvastatin daily as extended-release tablets (8 times the maximum recommended human oral daily dosage). Simvastatin dosages as high as 100 g/m² in dogs were associated with emesis and mucus in the stool.

Treatment

If acute statin overdosage occurs, supportive and symptomatic treatment should be initiated and the patient observed closely. Pending additional experience, specific recommendations for the management of statin overdosage currently are not available. It is not known whether statins or their metabolites are removed by hemodialysis or peritoneal dialysis. Some manufacturers state that these procedures are not expected to substantially enhance clearance of statins, since these agents (other than pravastatin) are extensively bound to plasma proteins.

Pharmacology

Statins are antilipemic agents that competitively inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid, an early precursor of cholesterol. These agents are structurally similar to HMG-CoA and produce selective, reversible, competitive inhibition of HMG-CoA reductase. The high affinity of statins for HMG-CoA reductase may result from their binding to 2 separate sites on the enzyme.

Antilipemic Effects

The antilipemic action of statins results from their inhibition of HMG-CoA reductase and subsequent reduction in hepatic cholesterol synthesis. In humans, biosynthesis of cholesterol from acetyl-CoA in the liver accounts for 60–70% of the total cholesterol pool. Thus, at usual therapeutic dosages, inhibition of HMG-CoA reductase (and subsequent mevalonic acid and cholesterol synthesis) by statins via this mechanism is incomplete, and adrenal and gonadal steroidogenesis are not affected substantially as evidenced by a lack of effect of statins on plasma cortisol concentrations.

Effects on Plasma Lipoprotein Concentrations

Statins reduce serum concentrations of low-density lipoprotein (LDL)-cholesterol, very low-density lipoprotein (VLDL)-cholesterol, apolipoprotein B (apo B), and triglycerides. The precise mechanisms by which statins reduce plasma LDL-cholesterol concentrations have not been fully elucidated but appear to be complex. Normally, the cell synthesizes cholesterol de novo for use in cell-membrane and steroid-hormone synthesis or obtains it from circulating low-density lipoproteins (LDLs) via receptor-mediated endocytosis. Most cholesterol in human serum is contained within LDL particles. Cellular cholesterol content is regulated by a feedback mechanism involving both cholesterol synthesis and the uptake and clearance of LDLs by LDL receptors, principally in the liver. Inhibition of hepatic cholesterol biosynthesis by statins results in a compensatory increase in the production of LDL receptors by cells in the liver; these receptors bind circulating LDLs and remove them from serum. In addition to the increased production of LDL receptors, in vitro and animal studies indicate that a simultaneous compensatory increase in the amount of HMG-CoA reductase in the liver occurs as a result of increased synthesis and/or decreased degradation of this enzyme. Production of LDLs also may be decreased by statins as a result of decreased hepatic production of VLDLs or increased binding and catabolism of VLDL remnants (i.e., intermediate-density lipoproteins, IDLs) by the LDL receptor, since VLDLs and VLDL remnants normally are converted to LDLs. Thus, LDL receptors are involved both in enhancing clearance and inhibiting production of LDLs. Inhibition of hepatic synthesis of apolipoprotein B (apo B), and thus the secretion of the apo B-containing LDLs and VLDLs, also has been suggested to account for some of the cholesterol- and triglyceride-lowering effects of statins. Statins produce modest increases in HDL-cholesterol and apolipoprotein A (apo A) concentrations. The mechanism by which statins increase HDL-cholesterol concentrations has not been fully elucidated but may be related to an increased synthesis of apo A-I.

Statins also have been shown to reduce hepatic lipase activity, increase LDL-cholesterol buoyancy, and decrease cholesteryl ester transfer protein (CETP) activity, alterations that may favorably influence coronary artery disease regression. Effects of statins on lipoprotein(a) (Lp[a]), fibrinogen, and certain other independent biochemical risk factors for coronary heart disease (CHD) have not been fully elucidated.

In patients with primary hypercholesterolemia or mixed dyslipidemia who received recommended daily dosages of various statins for at least 6 weeks, serum total and LDL-cholesterol concentrations were reduced by an average of 16–46 and 21–63%, respectively. Dose-related reductions in apo B (18–54%) and triglyceride (6–37%) concentrations, and small, variable increases in HDL-cholesterol concentrations (2–16%) also were observed in these patients. Patients with homozygous familial hypercholesterolemia have poorly functioning, few, or no LDL receptors and generally are much less responsive to statin therapy than those who have the heterozygous form of the disease; however, reductions of 14–46% in LDL-cholesterol concentrations have been reported in patients with homozygous familial hypercholesterolemia who received atorvastatin, rosuvastatin, or simvastatin. Reductions of 22–58% in serum total cholesterol, 27–57% in LDL-cholesterol, and 12–53% in triglyceride concentrations have occurred during therapy with various statins in patients with other primary types of hypercholesterolemia (including primary dysbetalipoproteinemia and hypertriglyceridemia). In most patients with primary hypercholesterolemia, marked reductions in serum lipoprotein and apolipoprotein concentrations occur within 1–2 weeks of initiating statin therapy, and maximal changes usually are observed within 4–6 weeks. Serum lipoprotein concentrations usually return to baseline levels within the same time period after discontinuance of the drug.

Tolerance to Antilipemic Effects

Development of clinically important tolerance to the cholesterol-lowering effects of statins does not appear to occur commonly, even in patients treated for several (e.g., 2–6) years with the drug. However, in some patients receiving monotherapy with a statin, small increases in serum total and LDL-cholesterol concentrations (compared with those observed early in therapy) have been noted after 1–2 years of therapy, and it has been suggested (in the absence of other identifiable causes such as changes in compliance with drug therapy or diet, other medical conditions) that compensatory increases in HMG-CoA reductase concentrations may be responsible for these minor increases.

Relative Potency

Results from clinical studies indicate that statins are not equipotent (on a weight basis) in their LDL-cholesterol-lowering effects. In clinical trials, the greatest reductions in LDL-cholesterol and triglyceride concentrations generally have been observed in patients receiving rosuvastatin. In a randomized, parallel-group study, rosuvastatin 10 mg produced LDL-cholesterol reductions that were similar to atorvastatin 20 or 40 mg and superior to atorvastatin 10 mg, pravastatin 40 mg, or simvastatin 40 mg. In another randomized, parallel-group study, atorvastatin 10 mg produced LDL-cholesterol reductions similar to or exceeding those produced by up to 40 mg of simvastatin, pravastatin, lovastatin, or fluvastatin. In several randomized studies, pitavastatin 1 mg produced LDL-cholesterol reductions that were superior to pravastatin 10 mg in geriatric patients; pitavastatin 2 mg produced LDL-cholesterol reductions that were noninferior to atorvastatin 10 mg, superior to simvastatin 20 mg, and superior to pravastatin 20 mg; pitavastatin 4 mg produced LDL-cholesterol reductions that were noninferior to atorvastatin 20 mg and simvastatin 40 mg, and superior to pravastatin 40 mg; pitavastatin 4 mg produced LDL-cholesterol reductions that were not noninferior to atorvastatin 20 mg in patients with type 2 diabetes. Some clinicians suggest that 20 mg of simvastatin is approximately equipotent to 40 mg of lovastatin or pravastatin or to 80 mg of fluvastatin. Others propose that simvastatin is approximately 3 times more potent than lovastatin or pravastatin and 8 times more potent than fluvastatin (i.e., with 5 mg of simvastatin being approximately equipotent to 15 mg of lovastatin or pravastatin or to 40 mg of fluvastatin).

Antiatherogenic Effects

Most statins have been shown to slow the progression and/or induce regression^† of atherosclerosis in coronary and/or carotid arteries. (See Reducing Progression of Coronary Atherosclerosis under Uses: Prevention of Cardiovascular Events.) The precise mechanism by which statins slow the progression of and/or induce regression of atherosclerotic lesions in patients with dyslipidemia has not been fully elucidated; however, limited evidence suggests that some of these effects of statins may be independent of their antilipemic effects.

Limited data from in vitro studies indicate that most statins may reduce intimal-medial wall thickness by producing a concentration-dependent inhibition of aortic or femoral arterial smooth muscle cell proliferation and/or inducing apoptosis of vascular smooth muscle cells. Pravastatin does not appear to exert such inhibition because the lower lipophilicity of the drug impairs its passive diffusion into extrahepatic cells; the ability of the drug to inhibit cholesterol synthesis like other statins is explained by its active transport into hepatocytes. Limited data from experimental studies suggest that statins also may stabilize atherosclerotic plaques by preventing oxidation of LDL-cholesterol, inhibiting macrophage cholesterol ester accumulation, and impairing the release of proteolytic enzymes (i.e., metalloproteases) that may weaken the fibrous cap and predispose plaques to rupture.

Vascular Effects

Statins have been reported to decrease blood pressure in patients with hypertension and primary hypercholesterolemia. In several small randomized, placebo-controlled studies, patients with moderate hypercholesterolemia and hypertension who received pravastatin (10–40 mg daily) or simvastatin (10–40 mg daily) for at least 12 weeks had mean reductions in systolic, diastolic, and pulse pressures of 7–8, 4–5, and 3 mm Hg, respectively, compared with those values in patients receiving placebo. The precise mechanism by which statins modulate blood pressure in hypercholesterolemic patients with hypertension has not been fully elucidated; however, some evidence suggests that these antihypertensive effects may be related to statin-induced restoration of endothelial dysfunction (i.e., increased arterial compliance), activation of endothelial nitric oxide synthase, and reduction of plasma aldosterone concentrations. Additional study is needed to determine the long-term antihypertensive effects, if any, of statins in patients with comorbid conditions, in patients with higher baseline blood pressure and cholesterol concentrations, and in patients receiving antihypertensive therapy.

Improvements in endothelium-dependent vasodilation, as evidenced by improved coronary blood flow, decreased peripheral resistance, increased myocardial perfusion, and increased cardiac output, have been reported in a limited number of normocholesterolemic or hypercholesterolemic patients who received statin therapy for at least 4 weeks. Although the mechanism of these vascular effects has not been fully elucidated, it has been suggested that such effects may result from increased expression of endothelial nitric oxide synthase (eNOS) and subsequently, release of nitric oxide, both of which may improve endothelial function in systemic and cerebral vasculatures.

Antithrombotic Effects

Conflicting data have been reported regarding the effects of statins on hemostatic abnormalities (i.e., prothrombotic state) associated with hypercholesterolemia. While some statins appear to inhibit platelet aggregation and tissue factor expression, none has been shown consistently to produce beneficial changes in plasminogen activator inhibitor-1 (PAI-1, the principal inhibitor of the fibrinolytic system), fibrinogen concentrations, or whole blood viscosity. However, in a large, randomized, placebo-controlled study (Heart and Estrogen/Progestin Replacement Study [HERS]) evaluating the effect of estrogen/progestin replacement therapy on coronary events (nonfatal myocardial infarction and coronary death) in postmenopausal women with CHD, the risk of venous thromboembolic disease (deep-vein thrombosis and pulmonary embolism) was reduced in patients receiving statin therapy compared with placebo recipients.

Anti-inflammatory Effects

Evidence from controlled and uncontrolled studies in hypercholesterolemic patients with or without documented CHD suggests that statins may possess anti-inflammatory activity. Data from retrospective and prospective studies in hypercholesterolemic patients with or without documented CHD indicate that statin therapy reduces plasma C-reactive protein (CRP) concentrations; CRP concentrations also were reduced among relatively normocholesterolemic patients with high baseline CRP levels. Effects on CRP concentrations do not appear to correlate with changes in LDL-cholesterol concentrations and are more pronounced in patients with high baseline C-reactive protein levels. Data from recent studies with statins indicate that lowering CRP concentrations may reduce the risk of recurrent MI or death from coronary causes in patients with acute coronary syndromes (ACS) or slow the progression of coronary atherosclerosis in patients with documented CHD.

Limited data indicate that statins also may exert neuroprotective effects by preventing induction of inducible nitric oxide synthase (iNOS) and attenuating inflammatory cytokine responses (e.g., interleukin-1 [IL-1], IL-6, tumor necrosis factor [TNF]-α), mechanisms that accompany tissue injury and cerebral ischemia.

Statins also have been shown to inhibit the growth of lymphocytes and other blood mononuclear cells; the clinical relevance of these effects has not been fully elucidated.

Effects on Bone

Limited data indicate that use of statins may be associated with an increase in bone mineral density. (See Uses: Other Uses.) The mechanism of this effect has not been fully elucidated but may be indirectly related to a decreased production of intermediate metabolites responsible for prenylation of proteins that regulate osteoclast cell processes.

Other Effects

Results of an observational study indicate a lower prevalence of Alzheimer’s disease among patients who received certain statins (i.e., lovastatin, pravastatin); however, the mechanism of these effects currently is not known.

HMG-CoA Reductase Inhibitors General Statement Pharmacokinetics

Plasma concentrations of statins have been measured using a radioenzymatic assay and, more recently, high-performance liquid chromatography (HPLC) or gas chromatography coupled with mass spectrometry (GC/MS) techniques. HPLC and GC/MS techniques, which directly measure plasma drug and metabolite concentrations, are more specific than the radioenzymatic assay, which reports concentrations of total active inhibitors by determining total HMG-CoA reductase inhibitory activity. It must be noted, however, that the antilipemic effects of statins correlate with dosage rather than with plasma concentrations of the drugs.

Absorption

Statins appear to be rapidly absorbed following oral administration and undergo extensive first-pass metabolism in the liver. The extent of absorption following oral administration varies considerably among statins. In animals, approximately 30–98% of oral radiolabeled doses of the drugs reaches systemic circulation. Because of extensive hepatic extraction, the amount of drug reaching systemic circulation as active inhibitors following oral administration in animals or humans is low; the absolute bioavailabilities of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin are 14, 24, 5, 51, 17, 20, and less than 5%, respectively. The mean relative bioavailability of the extended-release formulation of fluvastatin is approximately 29% compared with that of the immediate-release capsule administered under fasting conditions. The relative bioavailability of lovastatin following administration of the extended-release formulation is greater than that achieved with the immediate-release formulation; however, the bioavailability of total and active inhibitors of HMG-CoA reductase is similar between the 2 formulations.

Food appears to alter the systemic bioavailability of certain statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin) following oral administration. While administration of some statins (e.g., atorvastatin, immediate-release fluvastatin, extended-release lovastatin, pravastatin) with food results in small, clinically unimportant alterations in the rate and/or extent of absorption of these agents, optimal absorption of other statins (e.g., extended-release fluvastatin, lovastatin) may occur when the drugs are administered with food.

Some evidence suggests that plasma concentrations following oral administration of some statins may be related to circadian rhythms; evening administration of atorvastatin and pravastatin was associated with a 30–60% decrease in peak plasma concentrations and areas under the plasma-concentration time curve (AUCs). Despite the decrease in systemic bioavailability, the antilipemic activity of these statins following evening administration remains unchanged and appears to be marginally superior to that achieved with morning administration.

Mean peak plasma concentrations of active inhibitors occur at 1–5 hours following oral administration of conventional formulations of various statins. A therapeutic response to statins usually is apparent within 1–2 weeks after initiating therapy, with maximal changes in lipoprotein and apolipoprotein concentrations occurring within 4–6 weeks.

Peak plasma concentrations of some statins (e.g., atorvastatin, fluvastatin, pitavastatin) appear to be slightly higher in women than in men; however, such variability does not appear to correlate with the antilipemic activity of these drugs. It has been suggested that such variability may result from body weight differences since adjusting for body weight decreases the magnitude of the observed variation.

Limited data indicate that plasma concentrations of most statins may be higher in geriatric individuals (65 years of age and older) than in younger adults. Nevertheless, such alterations do not appear to alter the antilipemic effects of these statins.

The pharmacokinetics of statins are not altered substantially in patients with mild renal impairment (creatinine clearance of 61–90 mL/minute per 1.73 m²). However, increased plasma concentrations of lovastatin or rosuvastatin have been observed in patients with severe renal impairment (creatinine clearance of 10–30 mL/minute). The manufacturers of pravastatin and simvastatin state that patients with moderate to severe renal insufficiency may be predisposed to higher systemic exposure of these drugs and their metabolites. (See Cautions: Precautions and Contraindications.)

Some evidence indicates that certain statins may accumulate in the plasma of patients with hepatic impairment. (See Cautions: Hepatic Effects and see Precautions and Contraindications.) Mean peak plasma concentrations and AUCs of atorvastatin, fluvastatin, pitavastatin, pravastatin, and rosuvastatin are substantially higher and more variable in patients with hepatic insufficiency, chronic liver disease, or cirrhosis compared with those observed in healthy individuals.

Distribution

Distribution of statins into body tissues and fluids has not been fully characterized. All statins are distributed mainly to the liver, although distribution into extrahepatic tissues (e.g., spleen, kidney, adrenal glands) also has been reported with certain statins (e.g., lovastatin, pravastatin). Pitavastatin undergoes carrier-mediated uptake into hepatocytes, principally via organic anionic transport polypeptide (OATP) 1B1 (OATP2) and, to a lesser extent, by OATP1B3 and OATP2B1. Data from in vivo assays indicate that atorvastatin (which has a mean volume of distribution of 381 L) also may distribute into the spleen and adrenal glands.

With the exception of pravastatin, which is approximately 50% bound to human plasma proteins, all statins are 88–99% bound to human plasma proteins, principally albumin.

Results of studies in animals and humans indicate that statins may cross the placenta and distribute into milk. (See Cautions: Pregnancy, Fertility, and Lactation.) Some statins (e.g., lovastatin and simvastatin, which are lactones) have been shown to cross the blood-brain barrier, while other less lipophilic statins (e.g., fluvastatin, pravastatin) do not substantially distribute into the CNS.

Elimination

Statins are extensively metabolized, principally in the liver. Atorvastatin, lovastatin, and simvastatin appear to be metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, mainly by the isoenzyme 3A4 (CYP3A4). Fluvastatin is metabolized principally (approximately 75%) by CYP2C9, although CYP2C8 and CYP3A4 also may be involved (approximately 5 and 20%, respectively). Pitavastatin is principally metabolized by uridine 5′-diphosphate (UDP) glucuronosyltransferase (i.e., UGT1A1, UGT1A3, UGT2B7); the drug is minimally metabolized by CYP2C9 and CYP2C8. Pravastatin undergoes enzymatic and nonenzymatic biotransformation independent of the CYP microsomal enzyme system. Rosuvastatin is not extensively metabolized; approximately 10% of the drug is metabolized in the liver, principally by CYP2C9.

Atorvastatin, lovastatin, rosuvastatin, and simvastatin have active metabolites, while the principal metabolites of fluvastatin, pitavastatin, and pravastatin are pharmacologically inactive.

With the exception of atorvastatin, pitavastatin, and rosuvastatin (which have plasma elimination half-lives of 14, 12, and 19 hours, respectively), most statins have relatively short half-lives (between 0.5–3 hours); the elimination half-life of fluvastatin given as extended-release tablets is 9 hours. Despite differences in the mean elimination half-lives among statins, there appears to be little, if any, correlation between this pharmacokinetic parameter and duration of therapeutic effect (which reportedly is at least 24 hours for all statins).

There is no evidence of drug accumulation during repeated administration of most statins. However, systemic exposure to fluvastatin (administered as conventional capsules or extended-release tablets) appears to be increased following multiple oral doses of the drug. Because of its long plasma elimination half-life, atorvastatin may accumulate in plasma following administration of multiple oral doses.

Statins are excreted in urine and feces. Following oral administration of single radiolabeled doses of various statins, approximately 2–20% of the dose is excreted in urine and 60–90% in feces. Although renal excretion appears to be a minor route of elimination, the amount of drug eliminated via this route has been shown to reach 20% of the orally administered dose for pravastatin. Following IV administration of a radiolabeled dose of pravastatin in healthy individuals, approximately 47% of the drug was cleared from the blood by renal excretion and 53% was cleared by nonrenal mechanisms (e.g., biliary excretion, biotransformation). Statins do not appear to undergo enterohepatic recirculation.

It is not known whether statins or their metabolites are removed by hemodialysis or peritoneal dialysis. Some manufacturers state that these procedures are not expected to substantially enhance clearance of statins, since these agents (other than pravastatin) are extensively bound to plasma proteins.

Chemistry and Stability

Chemistry

Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are antilipemic agents that competitively inhibit HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid, an early precursor of cholesterol. Because of the similarity in their United States Adopted Names (USAN), HMG-CoA reductase inhibitors often are referred to as statins. This short-hand term also has been adopted by various experts (e.g., the National Institutes of Health, National Cholesterol Education Program, American College of Cardiology, American Heart Association) as a simplified means for referring to this class of antilipemic agents and is used throughout the HMG-CoA Reductase Inhibitors General Statement to simplify discussion.

Mevastatin (compactin, not commercially available) is the prototype of the statins, and all currently available statins were developed as structural derivatives of mevastatin. Statins are either fungus-derived (lovastatin, pravastatin, simvastatin) or are produced synthetically (atorvastatin, cerivastatin [no longer commercially available in the US], fluvastatin, pitavastatin, rosuvastatin). The fungus-derived compound lovastatin is a fermentation product of Aspergillus terreus, whereas pravastatin and simvastatin are produced by chemical modification of lovastatin. Fully synthetic statins exist either as racemic mixtures (fluvastatin) or as pure enantiomers (atorvastatin).

All commercially available statins contain a nucleus that interacts with the coenzyme A recognition site of HMG-CoA reductase and a β,δ-dihydroxy acid side chain that competes with HMG-CoA for interaction with HMG-CoA reductase. The nucleus is structurally distinct among fungus-derived and synthetic statins and consists of a hexahydronaphthalene moiety or an indole/pyrrole/pyridine moiety, respectively. Structural modification of the nucleus alters the lipophilicity of individual statin compounds. Among fungus-derived statins, substitution of a hydroxyl group for the methyl group on the hexahydronaphthalene ring of lovastatin produces a compound (i.e., pravastatin) with lower lipophilicity, while addition of a methyl group on the butyryl ester side chain produces one (i.e., simvastatin) with a more than twofold increase in lipophilicity, resulting in a greater potential for the latter compound to cross the blood-brain barrier. However, limited evidence indicates that these differences in lipophilicity do not appear to be clinically important. The β,δ-dihydroxy acid side chain (which is structurally similar to HMG-CoA and necessary for catalytic activity of HMG-CoA reductase) exists either as an active dihydroxy acid salt or an inactive lactone. Compounds possessing the dihydroxy acid salt (e.g., atorvastatin], fluvastatin, pitavastatin, pravastatin, rosuvastatin) are orally active, while those with the lactone moiety (e.g., lovastatin, simvastatin) are prodrugs and have little, if any, antilipemic activity until hydrolyzed in vivo to the corresponding ring-opened, β,δ-dihydroxy acid form.

Lovastatin and simvastatin are practically insoluble in water; atorvastatin is very slightly soluble in water; rosuvastatin is sparingly soluble in water and methanol, and slightly soluble in ethanol; and cerivastatin, fluvastatin, and pravastatin are each soluble in water. The solubilities of atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin in water are 0.11, greater than 195, 2, 0.0013, 300, and 0.0014 mg/mL, respectively. Pitavastatin is slightly soluble in methanol and very slightly soluble in water or ethanol.

Stability

Statins generally should be stored in well-closed, light-resistant containers at 5–30°C. When stored under these conditions, statins generally are stable for 24 months after the date of manufacture.

Releated Monographs

For additional information on chemistry and stability, uses, cautions, and dosage and administration of individual statins, see the individual monographs in 24:06.08.

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